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_______________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRILOSEC safely and effectively. See full prescribing information for
PRILOSEC.
PRILOSEC (omeprazole) Delayed-Release Capsules and PRILOSEC
(omeprazole magnesium)For Delayed-Release Oral Suspension
INITIAL U.S. APPROVAL: 1989
----------RECENT MAJOR CHANGES-------------
WARNINGS AND PRECAUTIONS
09/2010
Bone Fracture (5.3)
WARNINGS AND PRECAUTIONS
1/2011
Diminished anti-platelet activity of clopidogrel (5.4)
WARNINGS AND PRECAUTIONS
05/2011
Hypomagnesemia (5.7)
----------INDICATIONS AND USAGE-------------
PRILOSEC is a proton pump inhibitor (PPI) indicated for:
•
Treatment in adults of duodenal ulcer (1.1) and gastric ulcer (1.2)
•
Treatment in adults and children of gastroesophageal reflux disease
(GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4)
The safety and effectiveness of PRILOSEC in pediatric patients <1 year of
age have not been established. (8.4)
------DOSAGE AND ADMINISTRATION-----
Indication
Omeprazole Dose
Frequency
Treatment of Active
20 mg
Once daily for 4 weeks. Some
Duodenal Ulcer (2.1)
patients may require an
additional 4 weeks
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
Triple Therapy:
PRILOSEC
20 mg
Each drug twice daily for 10
Amoxicillin
1000 mg
days
Clarithromycin
500 mg
Dual Therapy:
PRILOSEC
40 mg
Once daily for 14 days
Clarithromycin
500 mg
Three times daily for 14 days
Gastric Ulcer (2.3)
40 mg
Once daily for 4 to 8 weeks
GERD (2.4)
20 mg
Once daily for 4 to 8 weeks
Maintenance of Healing of
20 mg
Once daily
Erosive Esophagitis (2.5)
Pathological Hypersecretory
60 mg (varies with
Once daily
Conditions (2.6)
individual patient)
Pediatric Patients
(1 to 16 years of age) (2.7)
Weight Dose
GERD And Maintenance
5 < 10 kg
5 mg
Once daily
of Healing of Erosive
10< 20 kg 10 mg
Esophagitis
> 20 kg
20 mg
-----DOSAGE FORMS AND STRENGTHS-----
•
PRILOSEC Delayed-Release Capsules, 10 mg, 20 mg and 40 mg (3)
•
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg (3)
-----------CONTRAINDICATIONS-----------------
Known hypersensitivity to any component of the formulation or substituted
benzimidazoles (angioedema and anaphylaxis have occurred) (4)
-------WARNINGS AND PRECAUTIONS-------
•
Symptomatic response does not preclude the presence of gastric
malignancy (5.1)
•
Atrophic gastritis: has been noted with long-term therapy (5.2)
•
Bone Fracture: Long-term and multiple daily dose PPI therapy may be
associated with an increased risk for osteoporosis-related fractures of the
hip, wrist or spine. (5.3)
•
Diminished anti-platelet activity of clopidogrel due to impaired
CYP2C19 function by 80 mg omeprazole (5.4)
•
Triple therapy for H. pylori – there are risks due to antibiotics; see
separate prescribing information for individual antibiotics (5.5, 5.6)
•
Hypomagnesemia has been reported rarely with prolonged treatment
with PPIs (5.7)
-----------ADVERSE REACTIONS-----------------
Adults: Most common adverse reactions in adults (incidence ≥ 2%) are
•
Headache, abdominal pain, nausea, diarrhea, vomiting, and
flatulence (6)
Pediatric patients (1 to 16 years of age):
Safety profile similar to that in adults, except that respiratory system
events and fever were the most frequently reported reactions in pediatric
studies (8.4)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------DRUG INTERACTIONS-----------------
•
May interfere with drugs for which gastric pH affects bioavailability
(e.g., ketoconazole, iron salts, ampicillin esters, and digoxin) (7.2)
•
Co-administration of clopidogrel with 80 mg omeprazole may reduce the
pharmacological activity of clopidogrel if given concomitantly or if
given 12 hours apart (7)
•
Atazanavir and nelfinavir: PRILOSEC reduces plasma levels of
atazanavir and nelfinavir. Concomitant use is not recommended (7.1)
•
Saquinavir: PRILOSEC increases plasma levels of saquinavir. Monitor
for toxicity and consider dose reduction of saquinavir (7.1)
•
Cilostazol: PRILOSEC increases systemic exposure of cilostazol and
one of its active metabolites. Consider dose reduction of cilostazol.(7.3)
•
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin,
phenytoin, cyclosporine, disulfiram, benzodiazepines): PRILOSEC can
prolong their elimination. Monitor and determine need for dose
adjustments (7.3)
•
Patients treated with proton pump inhibitors and warfarin may need to
be monitored for increases in INR and prothrombin time (7.3)
•
Tacrolimus: PRILOSEC may increase serum levels of tacrolimus (7.4)
•
Combined inhibitor of CYP 2C19 and 3A4 (e.g. voriconazole) may raise
omeprazole levels (7.3)
------USE IN SPECIFIC POPULATIONS----
Patients with hepatic impairment:
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis (12.3)
-----SEE 17 for Patient Counseling Information and FDA approved
Patient Labeling----
REVISED MAY 2011
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
1.2 Gastric Ulcer (adults)
1.3 Treatment of Gastroesophageal Reflux Disease (GERD)
(adults and pediatric patients)
1.4 Maintenance of Healing of Erosive Esophagitis (adults)
1.5 Pathological Hypersecretory Conditions
2
DOSAGE AND ADMINISTRATION
2.1 Short-Term Treatment of Active Duodenal Ulcer
2.2 H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
2.3 Gastric Ulcer
2.4 Gastroesophageal Reflux Disease (GERD)
2.5 Maintenance of Healing of Erosive Esophagitis
2.6 Pathological Hypersecretory Conditions
2.7 Pediatric Patients
2.8 Alternative Administration Options
2.9 Use with clopidogrel
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Concomitant Gastric Malignancy
5.2 Atrophic Gastritis
5.3 Bone Fracture
5.4 Diminished anti-platelet activity of clopidogrel due to
impaired CYP2C19 function by omeprazole
5.5 Combination Use of PRILOSEC with Amoxicillin
5.6 Combination Use of PRILOSEC with Clarithromycin
5.7 Hypomagnesemia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience with PRILOSEC Monotherapy
6.2 Clinical Trials Experience with PRILOSEC in Combination
Therapy for H. pylori Eradication
6.3 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Interference with Antiretroviral Therapy
7.2 Drugs for Which Gastric pH Can Affect Bioavailability
7.3
Effects on Hepatic Metabolism/Cytochrome P-450 Pathways
7.4 Tacrolimus
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Asian Population
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
14.2 Gastric Ulcer
14.3 Gastroesophageal Reflux Disease (GERD)
14.4 Erosive Esophagitis
14.5 Pathological Hypersecretory Conditions
14.6 Pediatric GERD
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
PRILOSEC is indicated for short-term treatment of active duodenal
ulcer in adults. Most patients heal within four weeks. Some patients
may require an additional four weeks of therapy.
PRILOSEC in combination with clarithromycin and amoxicillin, is
indicated for treatment of patients with H. pylori infection and
duodenal ulcer disease (active or up to 1-year history) to eradicate H.
pylori in adults.
PRILOSEC in combination with clarithromycin is indicated for
treatment of patients with H. pylori infection and duodenal ulcer
disease to eradicate H. pylori in adults.
Eradication of H. pylori has been shown to reduce the risk of
duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage
and Administration (2)].
Among patients who fail therapy, PRILOSEC with clarithromycin is
more likely to be associated with the development of clarithromycin
resistance as compared with triple therapy. In patients who fail
therapy, susceptibility testing should be done. If resistance to
clarithromycin is demonstrated or susceptibility testing is not
possible, alternative antimicrobial therapy should be instituted. [See
Microbiology section (12.4)], and the clarithromycin package insert,
Microbiology section.)
1.2 Gastric Ulcer (adults)
PRILOSEC is indicated for short-term treatment (4-8 weeks) of active
benign gastric ulcer in adults. [See Clinical Studies (14.2)]
1.3
Treatment of Gastroesophageal Reflux Disease
(GERD) (adults and pediatric patients)
Symptomatic GERD
PRILOSEC is indicated for the treatment of heartburn and other
symptoms associated with GERD in pediatric patients and adults.
Erosive Esophagitis
PRILOSEC is indicated for the short-term treatment (4-8 weeks) of
erosive esophagitis that has been diagnosed by endoscopy in pediatric
patients and adults. [See Clinical Studies (14.4)]
3
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of PRILOSEC used for longer than 8 weeks in these
patients has not been established. If a patient does not respond to 8
weeks of treatment, an additional 4 weeks of treatment may be given.
If there is recurrence of erosive esophagitis or GERD symptoms (eg,
heartburn), additional 4-8 week courses of omeprazole may be
considered.
1.4
Maintenance of Healing of Erosive Esophagitis
(adults and pediatric patients)
PRILOSEC is indicated to maintain healing of erosive esophagitis in
pediatric patients and adults.
Controlled studies do not extend beyond 12 months. [See Clinical
Studies (14.4)]
1.5
Pathological Hypersecretory Conditions (adults)
PRILOSEC is indicated for the long-term treatment of pathological
hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple
endocrine adenomas and systemic mastocytosis) in adults.
2
DOSAGE AND ADMINISTRATION
PRILOSEC Delayed-Release Capsules should be taken before eating.
In the clinical trials, antacids were used concomitantly with
PRILOSEC.
Patients should be informed that the PRILOSEC Delayed-Release
Capsule should be swallowed whole.
For patients unable to swallow an intact capsule, alternative
administration options are available [See Dosage and Administration
(2.8)].
2.1
Short-Term Treatment of Active Duodenal Ulcer
The recommended adult oral dose of PRILOSEC is 20 mg once daily.
Most patients heal within four weeks. Some patients may require an
additional four weeks of therapy.
2.2
H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin) — The
recommended adult oral regimen is PRILOSEC 20 mg plus
clarithromycin 500 mg plus amoxicillin 1000 mg each given twice
daily for 10 days. In patients with an ulcer present at the time of
initiation of therapy, an additional 18 days of PRILOSEC 20 mg once
daily is recommended for ulcer healing and symptom relief.
Dual Therapy (PRILOSEC/clarithromycin) — The recommended
adult oral regimen is PRILOSEC 40 mg once daily plus
clarithromycin 500 mg three times daily for 14 days. In patients with
an ulcer present at the time of initiation of therapy, an additional 14
4
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
days of PRILOSEC 20 mg once daily is recommended for ulcer
healing and symptom relief.
2.3
Gastric Ulcer
The recommended adult oral dose is 40 mg once daily for 4-8 weeks.
2.4
Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients with
symptomatic GERD and no esophageal lesions is 20 mg daily for up
to 4 weeks. The recommended adult oral dose for the treatment of
patients with erosive esophagitis and accompanying symptoms due to
GERD is 20 mg daily for 4 to 8 weeks.
2.5
Maintenance of Healing of Erosive Esophagitis
The recommended adult oral dose is 20 mg daily. [See Clinical
Studies (14.4)]
2.6
Pathological Hypersecretory Conditions
The dosage of PRILOSEC in patients with pathological
hypersecretory conditions varies with the individual patient. The
recommended adult oral starting dose is 60 mg once daily. Doses
should be adjusted to individual patient needs and should continue for
as long as clinically indicated. Doses up to 120 mg three times daily
have been administered. Daily dosages of greater than 80 mg should
be administered in divided doses. Some patients with Zollinger-
Ellison syndrome have been treated continuously with PRILOSEC for
more than 5 years.
2.7
Pediatric Patients
For the treatment of GERD and maintenance of healing of erosive
esophagitis, the recommended daily dose for pediatric patients 1 to
16 years of age is as follows:
Patient Weight
Omeprazole Daily Dose
5 < 10 kg
5 mg
10 < 20 kg
10 mg
> 20 kg
20 mg
On a per kg basis, the doses of omeprazole required to heal erosive
esophagitis in pediatric patients are greater than those for adults.
Alternative administrative options can be used for pediatric patients
unable to swallow an intact capsule [See Dosage and Administration
(2.8)].
2.8
Alternative Administration Options
PRILOSEC is available as a delayed-release capsule or as a delayed-
release oral suspension.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
5
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
2.9
Use with clopidogrel
Avoid concomitant use of clopidogrel and omeprazole. Co
administration of clopidogrel with 80 mg omeprazole, a proton pump
inhibitor that is an inhibitor of CYP2C19, reduces the
pharmacological activity of clopidogrel if given concomitantly or if
given 12 hours apart [see Warnings and Precautions (5.4) and Drug
Interactions (7.3)].
3
DOSAGE FORMS AND STRENGTHS
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body.
6
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body.
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body.
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules.
4
CONTRAINDICATIONS
PRILOSEC Delayed-Release Capsules are contraindicated in patients
with known hypersensitivity to substituted benzimidazoles or to any
component of the formulation. Hypersensitivity reactions may include
anaphylaxis,
anaphylactic
shock,
angioedema,
bronchospasm,
interstitial nephritis, and urticaria [See Adverse Reactions (6)].
5
WARNINGS AND PRECAUTIONS
5.1
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude
the presence of gastric malignancy.
5.2
Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus
biopsies from patients treated long-term with omeprazole.
5.3
Bone Fracture
Several published observational studies suggest that proton pump
inhibitor (PPI) therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as
multiple daily doses, and long-term PPI therapy (a year or longer).
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated. Patients at risk for
osteoporosis-related fractures should be managed according to
established treatment guidelines. [see Dosage and Administration (2)
and Adverse Reactions (6.3)]
5.4
Diminished Anti-platelet Activity of clopidogrel due
to Impaired CYP2C19 Function by Omeprazole
Clopidogrel is a prodrug. Inhibition of platelet aggregation by
clopidogrel is entirely due to an active metabolite. The metabolism of
clopidogrel to its active metabolite can be impaired by use with
concomitant medications, such as omeprazole, that interfere with
7
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CYP2C19 activity. Avoid concomitant use of clopidogrel and
omeprazole. Co-administration of clopidogrel with 80 mg
omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19,
reduces the pharmacological activity of clopidogrel if given
concomitantly or if given 12 hours apart [see Drug Interactions (7)].
5.5
Combination Use of PRILOSEC with Amoxicillin
Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions have been reported in patients on penicillin therapy. These
reactions are more likely to occur in individuals with a history of
penicillin hypersensitivity and/or a history of sensitivity to multiple
allergens. Before initiating therapy with amoxicillin, careful inquiry
should be made concerning previous hypersensitivity reactions to
penicillins, cephalosporins or other allergens. If an allergic reaction
occurs, amoxicillin should be discontinued and appropriate therapy
instituted. Serious anaphylactic reactions require immediate
emergency treatment with epinephrine. Oxygen, intravenous steroids
and airway management, including intubation, should also be
administered as indicated.
Pseudomembranous colitis has been reported with nearly all
antibacterial agents and may range in severity from mild to life-
threatening. Therefore, it is important to consider this diagnosis in
patients who present with diarrhea subsequent to the administration of
antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the
colon and may permit overgrowth of clostridia. Studies indicate that
a toxin produced by Clostridium difficile is a primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been
established, therapeutic measures should be initiated. Mild cases of
pseudomembranous colitis usually respond to discontinuation of the
drug alone. In moderate to severe cases, consideration should be
given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial drug clinically
effective against Clostridium difficile colitis.
5.6
Combination Use of PRILOSEC with Clarithromycin
Clarithromycin should not be used in pregnant women except in
clinical circumstances where no alternative therapy is appropriate. If
pregnancy occurs while taking clarithromycin, the patient should be
apprised of the potential hazard to the fetus. (See Warnings in
prescribing information for clarithromycin.)
Co-administration of omeprazole and clarithromycin has resulted in
increases in plasma levels of omeprazole, clarithromycin, and 14
hydroxy-clarithromycin. [See Clinical Pharmacology (12)]
8
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Concomitant administration of clarithromycin with cisapride or
pimozide, is contraindicated.
5.7
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported
rarely in patients treated with PPIs for at least three months, in most
cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of
hypomagnesemia required magnesium replacement and
discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs
with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), health care professionals may
consider monitoring magnesium levels prior to initiation of PPI
treatment and periodically. [See Adverse Reactions (6.3)]
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience with PRILOSEC
Monotherapy
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The safety data described below reflects exposure to PRILOSEC
Delayed-Release Capsules in 3096 patients from worldwide clinical
trials (465 patients from US studies and 2,631 patients from
international studies). Indications clinically studied in US trials
included duodenal ulcer, resistant ulcer, and Zollinger-Ellison
syndrome. The international clinical trials were double blind and
open-label in design. The most common adverse reactions reported
(i.e., with an incidence rate ≥ 2%) from PRILOSEC-treated patients
enrolled in these studies included headache (6.9%), abdominal pain
(5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and
flatulence (2.7%).
Additional adverse reactions that were reported with an incidence
≥1% included acid regurgitation (1.9%), upper respiratory infection
(1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia
(1.3%), back pain (1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age
was similar to that in patients 65 years of age or less.
The clinical trial safety profile in pediatric patients who received
PRILOSEC Delayed-Release Capsules was similar to that in adult
patients. Unique to the pediatric population, however, adverse
reactions of the respiratory system were most frequently reported in
9
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
both the 1 to <2 and 2 to 16 year age groups (75.0% and 18.5%,
respectively). Similarly, fever was frequently reported in the 1 to 2
year age group (33.0%), and accidental injuries were reported
frequently in the 2 to 16 year age group (3.8%). [See Use in Specific
Populations (8.4)]
6.2
Clinical Trials Experience with PRILOSEC in
Combination Therapy for H. pylori Eradication
In clinical trials using either dual therapy with PRILOSEC and
clarithromycin, or triple therapy with PRILOSEC, clarithromycin,
and amoxicillin, no adverse reactions unique to these drug
combinations were observed. Adverse reactions observed were
limited to those previously reported with omeprazole, clarithromycin,
or amoxicillin alone.
Dual Therapy (PRILOSEC/clarithromycin)
Adverse reactions observed in controlled clinical trials using
combination therapy with PRILOSEC and clarithromycin (n = 346)
that differed from those previously described for PRILOSEC alone
were taste perversion (15%), tongue discoloration (2%), rhinitis (2%),
pharyngitis (1%) and flu-syndrome (1%). (For more information on
clarithromycin, refer to the clarithromycin prescribing information,
Adverse Reactions section).
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)
The most frequent adverse reactions observed in clinical trials using
combination therapy with PRILOSEC, clarithromycin, and
amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%),
and headache (7%). None of these occurred at a higher frequency
than that reported by patients taking antimicrobial agents alone. (For
more information on clarithromycin or amoxicillin, refer to the
respective prescribing information, Adverse Reactions sections).
6.3
Post-marketing Experience
The following adverse reactions have been identified during post-
approval use of PRILOSEC Delayed-Release Capsules. Because
these reactions are voluntarily reported from a population of uncertain
size, it is not always possible to reliably estimate their actual
frequency or establish a causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions including anaphylaxis,
anaphylactic shock, angioedema, bronchospasm, interstitial nephritis,
urticaria, (see also Skin below); fever; pain; fatigue; malaise;
Cardiovascular: Chest pain or angina, tachycardia, bradycardia,
palpitations, elevated blood pressure, peripheral edema
Endocrine: Gynecomastia
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon,
fecal discoloration, esophageal candidiasis, mucosal atrophy of the
tongue, stomatitis, abdominal swelling, dry mouth. During treatment
with omeprazole, gastric fundic gland polyps have been noted rarely.
10
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These polyps are benign and appear to be reversible when treatment is
discontinued.
Gastroduodenal carcinoids have been reported in patients with ZE
syndrome on long-term treatment with PRILOSEC. This finding is
believed to be a manifestation of the underlying condition, which is
known to be associated with such tumors.
Hepatic: Liver disease including hepatic failure (some fatal), liver
necrosis (some fatal), hepatic encephalopathy hepatocellular disease,
cholestatic disease, mixed hepatitis, jaundice, and elevations of liver
function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
Metabolism and Nutritional disorders: Hypoglycemia,
hypomagnesemia, hyponatremia, weight gain
Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint
pain, leg pain, bone fracture
Nervous System/Psychiatric: Psychiatric and sleep disturbances
including depression, agitation, aggression, hallucinations, confusion,
insomnia, nervousness, apathy, somnolence, anxiety, and dream
abnormalities; tremors, paresthesia; vertigo
Respiratory: Epistaxis, pharyngeal pain
Skin: Severe generalized skin reactions including toxic epidermal
necrolysis (some fatal), Stevens-Johnson syndrome, and erythema
multiforme; photosensitivity; urticaria; rash; skin inflammation;
pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis
Special Senses: Tinnitus, taste perversion
Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic
neuritis, dry eye syndrome, ocular irritation, blurred vision, double
vision
Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated
serum creatinine, microscopic pyuria, urinary tract infection,
glycosuria, urinary frequency, testicular pain
Hematologic: Agranulocytosis (some fatal), hemolytic anemia,
pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia,
leucocytosis
7
DRUG INTERACTIONS
7.1
Interference with Antiretroviral Therapy
Concomitant use of atazanavir and nelfinavir with proton pump
inhibitors is not recommended. Co-administration of atazanavir with
proton pump inhibitors is expected to substantially decrease
atazanavir plasma concentrations and may result in a loss of
therapeutic effect and the development of drug resistance. Co
administration of saquinavir with proton pump inhibitors is expected
to increase saquinavir concentrations, which may increase toxicity
and require dose reduction.
Omeprazole has been reported to interact with some antiretroviral
drugs. The clinical importance and the mechanisms behind these
interactions are not always known. Increased gastric pH during
omeprazole treatment may change the absorption of the antiretroviral
drug. Other possible interaction mechanisms are via CYP 2C19.
11
Reference ID: 2950114
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Reduced concentrations of atazanavir and nelfinavir
For some antiretroviral drugs, such as atazanavir and nelfinavir,
decreased serum levels have been reported when given together with
omeprazole. Following multiple doses of nelfinavir (1250 mg, twice
daily) and omeprazole (40 mg daily), AUC was decreased by 36%
and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%
respectively for nelfinavir and M8. Following multiple doses of
atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before
atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by
95%. Concomitant administration with omeprazole and drugs such as
atazanavir and nelfinavir is therefore not recommended.
Increased concentrations of saquinavir
For other antiretroviral drugs, such as saquinavir, elevated serum
levels have been reported, with an increase in AUC by 82%, in Cmax
by 75%, and in Cmin by 106%, following multiple dosing of
saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with
omeprazole 40 mg daily co-administered days 11 to 15. Therefore,
clinical and laboratory monitoring for saquinavir toxicity is
recommended during concurrent use with PRILOSEC. Dose
reduction of saquinavir should be considered from the safety
perspective for individual patients.
There are also some antiretroviral drugs of which unchanged serum
levels have been reported when given with omeprazole.
7.2
Drugs for Which Gastric pH Can Affect
Bioavailability
Because of its profound and long lasting inhibition of gastric acid
secretion, it is theoretically possible that omeprazole may interfere
with absorption of drugs where gastric pH is an important
determinant of their bioavailability (e.g., ketoconazole, ampicillin
esters, and iron salts). In the clinical trials, antacids were used
concomitantly with the administration of PRILOSEC.
7.3
Effects on Hepatic Metabolism/Cytochrome P-450
Pathways
Omeprazole can prolong the elimination of diazepam, warfarin and
phenytoin, drugs that are metabolized by oxidation in the liver. There
have been reports of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including omeprazole, and warfarin
concomitantly. Increases in INR and prothrombin time may lead to
abnormal bleeding and even death. Patients treated with proton pump
inhibitors and warfarin may need to be monitored for increases in
INR and prothrombin time.
Although in normal subjects no interaction with theophylline or
propranolol was found, there have been clinical reports of interaction
12
Reference ID: 2950114
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For current labeling information, please visit https://www.fda.gov/drugsatfda
with other drugs metabolized via the cytochrome P450 system (e.g.,
cyclosporine, disulfiram, benzodiazepines). Patients should be
monitored to determine if it is necessary to adjust the dosage of these
drugs when taken concomitantly with PRILOSEC.
Concomitant administration of omeprazole and voriconazole (a
combined inhibitor of CYP2C19 and CYP3A4) resulted in more than
doubling of the omeprazole exposure. Dose adjustment of omeprazole
is not normally required. However, in patients with Zollinger-Ellison
syndrome, who may require higher doses up to 240 mg/day, dose
adjustment may be considered. When voriconazole (400 mg Q12h x 1
day, then 200 mg x 6 days) was given with omeprazole (40 mg once
daily x 7 days) to healthy subjects, it significantly increased the
steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times
(90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as
compared to when omeprazole was given without voriconazole.
Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in
doses of 40 mg daily for one week to 20 healthy subjects in cross
over study, increased Cmax and AUC of cilostazol by 18% and 26%
respectively. Cmax and AUC of one of its active metabolites, 3,4
dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were
increased by 29% and 69% respectively. Co-administration of
cilostazol with omeprazole is expected to increase concentrations of
cilostazol and its above mentioned active metabolite. Therefore a
dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d. should
be considered.
clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is
metabolized to its active metabolite in part by CYP2C19.
Concomitant use of omeprazole 80 mg results in reduced plasma
concentrations of the active metabolite of clopidogrel and a reduction
in platelet inhibition [see Warnings and Precautions (5.4)].
In a crossover clinical study, 72 healthy subjects were administered
clopidogrel (300 mg loading dose followed by 75 mg per day) alone
and with omeprazole (80 mg at the same time as clopidogrel) for 5
days. The exposure to the active metabolite of clopidogrel was
decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and
omeprazole were administered together. The active metabolite of
clopidogrel selectively and irreversibly inhibits the binding of
adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thereby
inhibiting platelet aggregation. The mean inhibition of platelet
aggregation at 5 mcM ADP was diminished by 39% (Day 1) and 21%
(Day 5) when clopidogrel and omeprazole were administered
together.
In another study, 72 healthy subjects were given the same doses of
clopidogrel and 80 mg omeprazole but the drugs were administered
13
Reference ID: 2950114
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12 hours apart; the results were similar, indicating that administering
clopidogrel and omeprazole at different times does not prevent their
interaction [see Warnings and Precautions (5.4)].
There are no adequate combination studies of a lower dose of
omeprazole or a higher dose of clopidogrel in comparison with the
approved dose of clopidogrel.
7.4
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may
increase the serum levels of tacrolimus.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Reproductive studies in rats and rabbits with omeprazole and multiple
cohort studies in pregnant women with omeprazole use during the
first trimester do not show an increased risk of congenital anomalies
or adverse pregnancy outcomes. There are no adequate and
well-controlled studies on the use of omeprazole in pregnant women.
Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if
clearly needed. The vast majority of reported experience with
omeprazole during human pregnancy is first trimester exposure and
the duration of use is rarely specified, e.g., intermittent vs. chronic.
An expert review of published data on experiences with omeprazole
use during pregnancy by TERIS – the Teratogen Information System
– concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (the quantity and quality of data
were assessed as fair).
Three epidemiological studies compared the frequency of congenital
abnormalities among infants born to women who used omeprazole
during pregnancy with the frequency of abnormalities among infants
of women exposed to H2-receptor antagonists or other controls. A
population-based prospective cohort epidemiological study from the
Swedish Medical Birth Registry, covering approximately 99% of
pregnancies, reported on 955 infants (824 exposed during the first
trimester with 39 of these exposed beyond first trimester, and 131
exposed after the first trimester) whose mothers used omeprazole
during pregnancy. In utero exposure to omeprazole was not
associated with increased risk of any malformation (odds ratio 0.82,
95% CI 0.50-1.34), low birth weight or low Apgar score. The
number of infants born with ventricular septal defects and the number
of stillborn infants was slightly higher in the omeprazole-exposed
infants than the expected number in the normal population. The
author concluded that both effects may be random.
A retrospective cohort study reported on 689 pregnant women
exposed to either H2-blockers or omeprazole in the first trimester (134
14
Reference ID: 2950114
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For current labeling information, please visit https://www.fda.gov/drugsatfda
exposed to omeprazole). The overall malformation rate was 4.4%
(95% CI 3.6-5.3) and the malformation rate for first trimester
exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk
of malformations associated with first trimester exposure to
omeprazole compared with non-exposed women was 0.9
(95% CI 0.3-2.2). The study could effectively rule out a relative risk
greater than 2.5 for all malformations. Rates of preterm delivery or
growth retardation did not differ between the groups.
A controlled prospective observational study followed 113 women
exposed to omeprazole during pregnancy (89% first trimester
exposures). The reported rates of major congenital malformations
was 4% for the omeprazole group, 2% for controls exposed to non-
teratogens, and 2.8% in disease-paired controls (background
incidence of major malformations 1-5%). Rates of spontaneous and
elective abortions, preterm deliveries, gestational age at delivery, and
mean birth weight did not differ between the groups. The sample size
in this study has 80% power to detect a 5-fold increase in the rate of
major malformation.
Several studies have reported no apparent adverse short-term effects
on the infant when single dose oral or intravenous omeprazole was
administered to over 200 pregnant women as premedication for
cesarean section under general anesthesia.
Reproductive studies conducted with omeprazole on rats at oral doses
up to 56 times the human dose and in rabbits at doses up to 56 times
the human dose did not show any evidence of teratogenicity. In
pregnant rabbits, omeprazole at doses about 5.5 to 56 times the
human dose produced dose-related increases in embryo-lethality, fetal
resorptions, and pregnancy loss. In rats treated with omeprazole at
doses about 5.6 to 56 times the human dose, dose-related
embryo/fetal toxicity and postnatal developmental toxicity occurred
in offspring. [See Animal Toxicology and/or Pharmacology (13.2)].
8.3
Nursing Mothers
Omeprazole concentrations have been measured in breast milk of a
woman following oral administration of 20 mg. The peak
concentration of omeprazole in breast milk was less than 7% of the
peak serum concentration. This concentration would correspond to
0.004 mg of omeprazole in 200 mL of milk. Because omeprazole is
excreted in human milk, because of the potential for serious adverse
reactions in nursing infants from omeprazole, and because of the
potential for tumorigenicity shown for omeprazole in rat
carcinogenicity studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
15
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.4
Pediatric Use
Use of PRILOSEC in pediatric and adolescent patients 1 to 16 years
of age for the treatment of GERD is supported by a) extrapolation of
results, already included in the currently approved labeling, from
adequate and well-controlled studies that supported the approval of
PRILOSEC for adults, and b) safety and pharmacokinetic studies
performed in pediatric and adolescent patients. [See Clinical
Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic
information (12.3) and Dosage and Administration (2), Adverse
Reactions (6.1) and Clinical Studies, (14.6)]. The safety and
effectiveness of PRILOSEC for the treatment of GERD in patients <1
year of age have not been established. The safety and effectiveness of
PRILOSEC for other pediatric uses have not been established.
8.5
Geriatric Use
Omeprazole was administered to over 2000 elderly individuals (≥ 65
years of age) in clinical trials in the U.S. and Europe. There were no
differences in safety and effectiveness between the elderly and
younger subjects. Other reported clinical experience has not
identified differences in response between the elderly and younger
subjects, but greater sensitivity of some older individuals cannot be
ruled out.
Pharmacokinetic studies have shown the elimination rate was
somewhat decreased in the elderly and bioavailability was increased.
The plasma clearance of omeprazole was 250 mL/min (about half that
of young volunteers) and its plasma half-life averaged one hour, about
twice that of young healthy volunteers. However, no dosage
adjustment is necessary in the elderly. [See Clinical Pharmacology
(12.3)]
8.6
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
8.7
Renal Impairment
No dosage reduction is necessary. [See Clinical Pharmacology
(12.3)]
8.8
Asian Population
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
10
OVERDOSAGE
Reports have been received of overdosage with omeprazole in
humans. Doses ranged up to 2400 mg (120 times the usual
recommended clinical dose). Manifestations were variable, but
included confusion, drowsiness, blurred vision, tachycardia, nausea,
vomiting, diaphoresis, flushing, headache, dry mouth, and other
adverse reactions similar to those seen in normal clinical experience.
16
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
[See Adverse Reactions (6)] Symptoms were transient, and no serious
clinical outcome has been reported when PRILOSEC was taken
alone. No specific antidote for omeprazole overdosage is known.
Omeprazole is extensively protein bound and is, therefore, not readily
dialyzable. In the event of overdosage, treatment should be
symptomatic and supportive.
As with the management of any overdose, the possibility of multiple
drug ingestion should be considered. For current information on
treatment of any drug overdose, contact a Poison Control Center at 1
800-222-1222.
Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were
lethal to mice, rats, and dogs, respectively. Animals given these doses
showed sedation, ptosis, tremors, convulsions, and decreased activity,
body temperature, and respiratory rate and increased depth of
respiration.
11
DESCRIPTION
The active ingredient in PRILOSEC (omeprazole) Delayed-Release
Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy
3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a
compound that inhibits gastric acid secretion. Its empirical formula is
C17H19N3O3S, with a molecular weight of 345.42. The structural
formula is: structural formula
Omeprazole is a white to off-white crystalline powder that melts with
decomposition at about 155°C. It is a weak base, freely soluble in
ethanol and methanol, and slightly soluble in acetone and isopropanol
and very slightly soluble in water. The stability of omeprazole is a
function of pH; it is rapidly degraded in acid media, but has
acceptable stability under alkaline conditions.
The active ingredient in PRILOSEC (omeprazole magnesium) for
Delayed Release Oral Suspension, is 5-Methoxy-2-[[(4-methoxy-3,5
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium
salt (2:1)
Omeprazole magnesium is a white to off white powder with a melting
point with degradation at 200°C. The salt is slightly soluble (0.25
mg/mL) in water at 25°C, and it is soluble in methanol. The half-life
is highly pH dependent.
17
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The empirical formula for omeprazole magnesium is (C17H18N3O3S)2
Mg, the molecular weight is 713.12 and the structural formula is: structural formula
PRILOSEC is supplied as delayed-release capsules for oral
administration. Each delayed-release capsule contains either 10 mg,
20 mg or 40 mg of omeprazole in the form of enteric-coated granules
with the following inactive ingredients: cellulose, disodium hydrogen
phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate and other ingredients. The capsule shells have
the following inactive ingredients: gelatin-NF, FD&C Blue #1,
FD&C Red #40, D&C Red #28, titanium dioxide, synthetic black iron
oxide, isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7
Calcium Lake, and, in addition, the 10 mg and 40 mg capsule shells
also contain D&C Yellow #10.
Each packet of PRILOSEC For Delayed-Release Oral Suspension
contains either 2.8 mg or 11.2 mg of omeprazole magnesium
(equivalent to 2.5 mg or 10 mg of omeprazole), in the form of enteric-
coated granules with the following inactive ingredients: glyceryl
monostearate, hydroxypropyl cellulose, hypromellose, magnesium
stearate, methacrylic acid copolymer C, polysorbate, sugar spheres,
talc, and triethyl citrate, and also inactive granules. The inactive
granules are composed of the following ingredients: citric acid,
crospovidone, dextrose, hydroxypropyl cellulose, iron oxide and
xantham gum. The omeprazole granules and inactive granules are
constituted with water to form a suspension and are given by oral,
nasogastric or direct gastric administration.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Omeprazole belongs to a class of antisecretory compounds, the
substituted benzimidazoles, that suppress gastric acid secretion by
specific inhibition of the H+/K+ ATPase enzyme system at the
secretory surface of the gastric parietal cell. Because this enzyme
system is regarded as the acid (proton) pump within the gastric
mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect
is dose-related and leads to inhibition of both basal and stimulated
acid secretion irrespective of the stimulus. Animal studies indicate
that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
18
Reference ID: 2950114
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.2 Pharmacodynamics
Antisecretory Activity
After oral administration, the onset of the antisecretory effect of
omeprazole occurs within one hour, with the maximum effect
occurring within two hours. Inhibition of secretion is about 50% of
maximum at 24 hours and the duration of inhibition lasts up to 72
hours. The antisecretory effect thus lasts far longer than would be
expected from the very short (less than one hour) plasma half-life,
apparently due to prolonged binding to the parietal H+/K+ ATPase
enzyme. When the drug is discontinued, secretory activity returns
gradually, over 3 to 5 days. The inhibitory effect of omeprazole on
acid secretion increases with repeated once-daily dosing, reaching a
plateau after four days.
Results from numerous studies of the antisecretory effect of multiple
doses of 20 mg and 40 mg of omeprazole in normal volunteers and
patients are shown below. The “max” value represents determinations
at a time of maximum effect (2-6 hours after dosing), while “min”
values are those 24 hours after the last dose of omeprazole.
Table 1
Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole
After Multiple Daily Dosing
Omeprazole
Omeprazole
Parameter
20 mg
40 mg
% Decrease in Basal Acid
Output
Max
78*
Min
58-80
Max
94*
Min
80-93
% Decrease in Peak Acid
Output
79*
50-59
88*
62-68
% Decrease in 24-hr.
Intragastric Acidity
80-97
92-94
*Single Studies
Single daily oral doses of omeprazole ranging from a dose of 10 mg
to 40 mg have produced 100% inhibition of 24-hour intragastric
acidity in some patients.
Serum Gastric Effects
In studies involving more than 200 patients, serum gastrin levels
increased during the first 1 to 2 weeks of once-daily administration of
therapeutic doses of omeprazole in parallel with inhibition of acid
secretion. No further increase in serum gastrin occurred with
continued treatment. In comparison with histamine H2-receptor
antagonists, the median increases produced by 20 mg doses of
omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase).
Gastrin values returned to pretreatment levels, usually within 1 to 2
weeks after discontinuation of therapy.
Enterochromaffin-like (ECL) Cell Effects
19
Reference ID: 2950114
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Human gastric biopsy specimens have been obtained from more than
3000 patients treated with omeprazole in long-term clinical trials. The
incidence of ECL cell hyperplasia in these studies increased with
time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia
has been found in these patients. [See Clinical Pharmacology (12)]
However, these studies are of insufficient duration and size to rule out
the possible influence of long-term administration of omeprazole on
the development of any premalignant or malignant conditions.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and
respiratory systems have not been found to date. Omeprazole, given
in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid
function, carbohydrate metabolism, or circulating levels of
parathyroid hormone, cortisol, estradiol, testosterone, prolactin,
cholecystokinin or secretin.
No effect on gastric emptying of the solid and liquid components of a
test meal was demonstrated after a single dose of omeprazole 90 mg.
In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had
no effect on intrinsic factor secretion. No systematic dose-dependent
effect has been observed on basal or stimulated pepsin output in
humans.
However, when intragastric pH is maintained at 4.0 or above, basal
pepsin output is low, and pepsin activity is decreased.
As do other agents that elevate intragastric pH, omeprazole
administered for 14 days in healthy subjects produced a significant
increase in the intragastric concentrations of viable bacteria. The
pattern of the bacterial species was unchanged from that commonly
found in saliva. All changes resolved within three days of stopping
treatment.
The course of Barrett’s esophagus in 106 patients was evaluated in a
U.S. double-blind controlled study of PRILOSEC 40 mg twice daily
for 12 months followed by 20 mg twice daily for 12 months or
ranitidine 300 mg twice daily for 24 months. No clinically significant
impact on Barrett’s mucosa by antisecretory therapy was observed.
Although neosquamous epithelium developed during antisecretory
therapy, complete elimination of Barrett’s mucosa was not achieved.
No significant difference was observed between treatment groups in
development of dysplasia in Barrett’s mucosa and no patient
developed esophageal carcinoma during treatment. No significant
differences between treatment groups were observed in development
of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal
metaplasia, or colon polyps exceeding 3 mm in diameter [See Clinical
Pharmacology (12)].
20
Reference ID: 2950114
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12.3 Pharmacokinetics
Absorption
PRILOSEC Delayed-Release Capsules contain an enteric-coated
granule formulation of omeprazole (because omeprazole is acid-
labile), so that absorption of omeprazole begins only after the
granules leave the stomach. Absorption is rapid, with peak plasma
levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma
concentrations of omeprazole and AUC are approximately
proportional to doses up to 40 mg, but because of a saturable first-
pass effect, a greater than linear response in peak plasma
concentration and AUC occurs with doses greater than 40 mg.
Absolute bioavailability (compared with intravenous administration)
is about 30-40% at doses of 20-40 mg, due in large part to
presystemic metabolism. In healthy subjects the plasma half-life is 0.5
to 1 hour, and the total body clearance is 500-600 mL/min.
Based on a relative bioavailability study, the AUC and Cmax of
PRILOSEC (omeprazole magnesium) for Delayed-Release Oral
Suspension were 87% and 88% of those for PRILOSEC Delayed-
Release Capsules, respectively.
The bioavailability of omeprazole increases slightly upon repeated
administration of PRILOSEC Delayed-Release Capsules.
PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when
administered with and without applesauce. However, PRILOSEC
Delayed-Release Capsule 20 mg was not bioequivalent when
administered with and without applesauce. When administered with
applesauce, a mean 25% reduction in Cmax was observed without a
significant change in AUC for PRILOSEC Delayed-Release Capsule
20 mg. The clinical relevance of this finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450
(CYP) enzyme system.
Excretion
Following single dose oral administration of a buffered solution of
omeprazole, little if any unchanged drug was excreted in urine. The
majority of the dose (about 77%) was eliminated in urine as at least
six metabolites. Two were identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was
recoverable in feces. This implies a significant biliary excretion of the
metabolites of omeprazole. Three metabolites have been identified in
plasma — the sulfide and sulfone derivatives of omeprazole, and
hydroxyomeprazole. These metabolites have very little or no
antisecretory activity.
21
Reference ID: 2950114
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Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with
clarithromycin 500 mg every 8 hours to healthy adult male subjects.
The steady state plasma concentrations of omeprazole were increased
(Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34%
respectively) by the concomitant administration of clarithromycin.
The observed increases in omeprazole plasma concentration were
associated with the following pharmacological effects. The mean 24
hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin
were increased by the concomitant administration of omeprazole. For
clarithromycin, the mean Cmax was 10% greater, the mean Cmin was
27% greater, and the mean AUC0-8 was 15% greater when
clarithromycin was administered with omeprazole than when
clarithromycin was administered alone. Similar results were seen for
14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean
Cmin was 57% greater, and the mean AUC0-8 was 45% greater.
Clarithromycin concentrations in the gastric tissue and mucus were
also increased by concomitant administration of omeprazole.
Table 2
Clarithromycin Tissue Concentrations
2 hours after Dose
1
Clarithromycin +
Tissue
Clarithromycin
Omeprazole
Antrum
10.48 ± 2.01 (n = 5)
19.96 ± 4.71 (n = 5)
Fundus
20.81 ± 7.64 (n = 5)
24.25 ± 6.37 (n = 5)
Mucus
4.15 ± 7.74 (n = 4)
39.29 ± 32.79 (n = 4)
1Mean ± SD (μg/g)
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the
elderly, and bioavailability was increased. Omeprazole was 76%
bioavailable when a single 40 mg oral dose of omeprazole (buffered
solution) was administered to healthy elderly volunteers, versus 58%
in young volunteers given the same dose. Nearly 70% of the dose was
recovered in urine as metabolites of omeprazole and no unchanged
drug was detected. The plasma clearance of omeprazole was 250
mL/min (about half that of young volunteers) and its plasma half-life
averaged one hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in
pediatric patients 2 to 16 years of age:
Table 3
22
Reference ID: 2950114
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Pharmacokinetic Parameters of Omeprazole Following Single
and Repeated Oral Administration in Pediatric Populations
Compared with Adults
Single or
Children†
Children†
Adults‡
Repeated
< 20 kg
> 20 kg
(mean
Oral Dosing
2-5 years
6-16
76 kg)
/Parameter
10 mg
years
23-29
20 mg
years
(n=12)
Single Dosing
Cmax *
288
495
668
(ng/mL)
(n=10)
(n=49)
AUC*
511
1140
1220
(ng h/mL)
(n=7)
(n=32)
Repeated Dosing
Cmax *
539
851
1458
(ng/mL)
(n=4)
(n=32)
AUC*
1179
2276
3352
(ng h/mL)
(n=2)
(n=23)
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
†Data from single and repeated dose studies
‡Data from a single and repeated dose study
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children
(2 to 5 years of age) have lower AUCs than children 6 to 16 years of
age or adults; AUCs of the latter two groups did not differ. [See
Dosage and Administration (2)]
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased
to approximately 100% compared with an I.V. dose, reflecting
decreased first-pass effect, and the plasma half-life of the drug
increased to nearly 3 hours compared with the half-life in normals of
0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a
value of 500-600 mL/min in normal subjects. Dose reduction,
particularly where maintenance of healing of erosive esophagitis is
indicated, for the hepatically impaired should be considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance
ranged between 10 and 62 mL/min/1.73 m2, the disposition of
omeprazole was very similar to that in healthy volunteers, although
there was a slight increase in bioavailability. Because urinary
excretion is a primary route of excretion of omeprazole metabolites,
their elimination slowed in proportion to the decreased creatinine
clearance. No dose reduction is necessary in patients with renal
impairment.
Asian Population
23
Reference ID: 2950114
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In pharmacokinetic studies of single 20 mg omeprazole doses, an
increase in AUC of approximately four-fold was noted in Asian
subjects compared with Caucasians. Dose reduction, particularly
where maintenance of healing of erosive esophagitis is indicated, for
Asian subjects should be considered.
12.4 Microbiology
Omeprazole and clarithromycin dual therapy and omeprazole,
clarithromycin and amoxicillin triple therapy have been shown to be
active against most strains of Helicobacter pylori in vitro and in
clinical infections as described in the Indications and Usage section
(1.1).
Helicobacter
Helicobacter pylori- Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the
omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3%
(41/439) in omeprazole/clarithromycin/amoxicillin triple therapy
studies (1, 2, and 3).
Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were
found in 99.3% (436/439) of the patients in the
omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2,
and 3). Amoxicillin pretreatment minimum inhibitory concentrations
(MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of
whom were in the clarithromycin and amoxicillin study arm. One
patient had an unconfirmed pretreatment amoxicillin minimum
inhibitory concentration (MIC) of > 256 µg/mL by Etest®.
Table 4
Clarithromycin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a
Clarithromycin Pretreatment Results
Clarithromycin Post-treatment Results
H. pylori negative –
eradicated
H. pylori positive – not eradicated
Post-treatment susceptibility results
S b
I b
R b
No MIC
Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed
by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5)
Susceptible b
108
72
1
26
9
Intermediate b
1
1
Resistant b
4
4
Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice
daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies
1, 2)
Susceptible b
171
153
7
3
8
Intermediateb
Resistant b
14
4
1
6
3
aIncludes only patients with pretreatment clarithromycin susceptibility test results
bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC 0.5 – 1.0 µg/mL, Resistant (R) MIC ≥ 2
μg/mL
24
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Patients not eradicated of H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy or
omeprazole/clarithromycin dual therapy will likely have
clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with
clarithromycin resistant H. pylori should not be treated with any of
the following: omeprazole/clarithromycin dual therapy,
omeprazole/clarithromycin/amoxicillin triple therapy, or other
regimens which include clarithromycin as the sole antimicrobial
agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
In the triple therapy clinical trials, 84.9% (157/185) of the patients in
the omeprazole/clarithromycin/amoxicillin treatment group who had
pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were
eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment
susceptibility test results and 17 had post-treatment H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed
triple therapy also had post-treatment H. pylori isolates with
clarithromycin resistant MICs.
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H. pylori is
agar dilution MICs1. One to three microliters of an inoculum
equivalent to a No. 2 McFarland standard (1 x 107 - 1 x 108 CFU/mL
for H. pylori) are inoculated directly onto freshly prepared
antimicrobial containing Mueller-Hinton agar plates with 5% aged
defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are
incubated at 35°C in a microaerobic environment produced by a gas
generating system suitable for campylobacters. After 3 days of
incubation, the MICs are recorded as the lowest concentration of
antimicrobial agent required to inhibit growth of the organism. The
clarithromycin and amoxicillin MIC values should be interpreted
according to the following criteria:
Table 5
Clarithromycin MIC (µg/mL) a
Interpretation
< 0.25
Susceptible (S)
0.5
Intermediate (I)
> 1.0
Resistant
(R)
Amoxicillin MIC (µg/mL) a,b
Interpretation
<0.25
Susceptible (S)
a These are tentative breakpoints for the agar dilution methodology and they should not be used to
interpret results obtained using alternative methods.
b There were not enough organisms with MICs > 0.25 µg/mL to determine a resistance breakpoint.
Standardized susceptibility test procedures require the use of
laboratory control microorganisms to control the technical aspects of
25
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the laboratory procedures. Standard clarithromycin and amoxicillin
powders should provide the following MIC values:
Microorganism
Antimicrobial Agent
MIC (µg/mL) a
H. pylori ATCC 43504
Clarithromycin
0.016- 0.12 (µg/mL)
H. pylori ATCC 43504
Amoxicillin
0.016- 0.12 (µg/mL)
aThese are quality control ranges for the agar dilution methodology and they should not be used to
control test results obtained using alternative methods.
Effects on Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including proton pump
inhibitors, increases gastric counts of bacteria normally present in the
gastrointestinal tract. Treatment with proton pump inhibitors may
lead to slightly increased risk of gastrointestinal infections such as
Salmonella and Campylobacter and possibly Clostridium difficile in
hospitalized patients.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily
doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57
times a human dose of 20 mg/day, as expressed on a body surface
area basis) produced gastric ECL cell carcinoids in a dose-related
manner in both male and female rats; the incidence of this effect was
markedly higher in female rats, which had higher blood levels of
omeprazole. Gastric carcinoids seldom occur in the untreated rat. In
addition, ECL cell hyperplasia was present in all treated groups of
both sexes. In one of these studies, female rats were treated with 13.8
mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day,
based on body surface area) for one year, and then followed for an
additional year without the drug. No carcinoids were seen in these
rats. An increased incidence of treatment-related ECL cell hyperplasia
was observed at the end of one year (94% treated vs 10% controls).
By the second year the difference between treated and control rats
was much smaller (46% vs 26%) but still showed more hyperplasia in
the treated group. Gastric adenocarcinoma was seen in one rat (2%).
No similar tumor was seen in male or female rats treated for two
years. For this strain of rat no similar tumor has been noted
historically, but a finding involving only one tumor is difficult to
interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain
astrocytomas were found in a small number of males that received
omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to
6.5 times the human dose on a body surface area basis). No
astrocytomas were observed in female rats in this study. In a 2-year
carcinogenicity study in Sprague-Dawley rats, no astrocytomas were
found in males or females at the high dose of 140.8 mg/kg/day (about
57 times the human dose on a body surface area basis). A 78-week
mouse carcinogenicity study of omeprazole did not show increased
tumor occurrence, but the study was not conclusive. A 26-week p53
(+/-) transgenic mouse carcinogenicity study was not positive.
26
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Omeprazole was positive for clastogenic effects in an in vitro human
lymphocyte chromosomal aberration assay, in one of two in vivo
mouse micronucleus tests, and in an in vivo bone marrow cell
chromosomal aberration assay. Omeprazole was negative in the in
vitro Ames test, an in vitro mouse lymphoma cell forward mutation
assay, and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times
the human dose on a body surface area basis) was found to have no
effect on fertility and reproductive performance.
In 24-month carcinogenicity studies in rats, a dose-related significant
increase in gastric carcinoid tumors and ECL cell hyperplasia was
observed in both male and female animals [See Warnings and
Precautions (5)] Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other proton
pump inhibitors or high doses of H2-receptor antagonists.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproductive studies conducted with omeprazole in rats at oral doses
up to 138 mg/kg/day (about 56 times the human dose on a body
surface area basis) and in rabbits at doses up to 69 mg/kg/day (about
56 times the human dose on a body surface area basis) did not
disclose any evidence for a teratogenic potential of omeprazole. In
rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about
5.5 to 56 times the human dose on a body surface area basis)
produced dose-related increases in embryo-lethality, fetal resorptions,
and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity
and postnatal developmental toxicity were observed in offspring
resulting from parents treated with omeprazole at 13.8 to 138.0
mg/kg/day (about 5.6 to 56 times the human doses on a body surface
area basis).
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
Active Duodenal Ulcer— In a multicenter, double-blind, placebo-
controlled study of 147 patients with endoscopically documented
duodenal ulcer, the percentage of patients healed (per protocol) at 2
and 4 weeks was significantly higher with PRILOSEC 20 mg once
daily than with placebo (p ≤ 0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Placebo
20 mg a.m.
a.m.
(n = 99)
(n = 48)
Week 2
*
13
41
Week 4
27
* 75
27
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*(p < 0.01)
Complete daytime and nighttime pain relief occurred significantly
faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in
patients treated with placebo. At the end of the study, significantly
more patients who had received PRILOSEC had complete relief of
daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).
In a multicenter, double-blind study of 293 patients with
endoscopically documented duodenal ulcer, the percentage of patients
healed (per protocol) at 4 weeks was significantly higher with
PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p <
0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
Week 2
Week 4
PRILOSEC
20 mg a.m.
(n = 145)
42
*82
Ranitidine
150 mg twice daily
(n = 148)
34
63
*(p < 0.01)
Healing occurred significantly faster in patients treated with
PRILOSEC than in those treated with ranitidine 150 mg b.i.d. (p <
0.01).
In a foreign multinational randomized, double-blind study of 105
patients with endoscopically documented duodenal ulcer, 20 mg and
40 mg of PRILOSEC were compared with 150 mg b.i.d. of ranitidine
at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were
statistically superior (per protocol) to ranitidine, but 40 mg was not
superior to 20 mg of PRILOSEC, and at 8 weeks there was no
significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg
40 mg
150 mg twice
(n = 34)
(n = 36)
daily
(n = 35)
Week 2
*83
*83
53
Week 4
82
*97
*100
Week 8
94
100
100
*(p < 0.01)
H. pylori Eradication in Patients with Duodenal Ulcer
Disease
Triple Therapy(PRILOSEC/clarithromycin/amoxicillin)— Three
U.S., randomized, double-blind clinical studies in patients with H.
pylori infection and duodenal ulcer disease (n = 558) compared
PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin
plus amoxicillin. Two studies (1 and 2) were conducted in patients
28
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with an active duodenal ulcer, and the other study (3) was conducted
in patients with a history of a duodenal ulcer in the past 5 years but
without an ulcer present at the time of enrollment. The dose regimen
in the studies was PRILOSEC 20 mg twice daily plus clarithromycin
500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or
clarithromycin 500 mg. twice daily plus amoxicillin 1 g twice daily
for 10 days. In studies 1 and 2, patients who took the omeprazole
regimen also received an additional 18 days of PRILOSEC 20 mg
once daily. Endpoints studied were eradication of H. pylori and
duodenal ulcer healing (studies 1 and 2 only). H. pylori status was
determined by CLOtest®, histology and culture in all three studies.
For a given patient, H. pylori was considered eradicated if at least two
of these tests were negative, and none was positive.
The combination of omeprazole plus clarithromycin plus amoxicillin
was effective in eradicating H. pylori.
Table 6
Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
% of Patients Cured [95% Confidence Interval]
PRILOSEC +clarithromycin
Clarithromycin +amoxicillin
+amoxicillin
Per-Protocol †
Intent-to-Treat ‡
Per-Protocol † Intent-to-Treat ‡
Study 1
*77 [64, 86]
(n = 64)
*69 [57, 79]
(n = 80)
43 [31, 56]
(n = 67)
37 [27, 48]
(n = 84)
Study 2
*78 [67, 88]
(n = 65)
*73 [61, 82]
(n = 77)
41 [29, 54]
(n = 68)
36 [26, 47]
(n = 83)
Study 3
*90 [80, 96]
(n = 69)
*83 [74, 91]
(n = 84)
33 [24, 44]
(n = 93)
32 [23, 42]
(n = 99)
† Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer
within 5 years, study 3) and H. pylori infection at baseline defined as
at least two of three positive endoscopic tests from CLOtest® ,
histology, and/or culture. Patients were included in the analysis if
they completed the study. Additionally, if patients dropped out of
the study due to an adverse event related to the study drug, they were
included in the analysis as failures of therapy. The impact of
eradication on ulcer recurrence has not been assessed in patients with
a past history of ulcer.
‡ Patients were included in the analysis if they had documented
H. pylori infection at baseline and had confirmed duodenal ulcer
disease. All dropouts were included as failures of therapy.
* (p < 0.05) versus clarithromycin plus amoxicillin.
Dual Therapy (PRILOSEC/clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7)
evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg
three times daily for 14 days, followed by PRILOSEC 20 mg once
daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study
6) for an additional 14 days in patients with active duodenal ulcer
associated with H. pylori. Studies 4 and 5 were conducted in the U.S.
and Canada and enrolled 242 and 256 patients, respectively. H. pylori
29
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infection and duodenal ulcer were confirmed in 219 patients in Study
4 and 228 patients in Study 5. These studies compared the
combination regimen to PRILOSEC and clarithromycin
monotherapies. Studies 6 and 7 were conducted in Europe and
enrolled 154 and 215 patients, respectively. H. pylori infection and
duodenal ulcer were confirmed in 148 patients in study 6 and 208
patients in Study 7. These studies compared the combination regimen
with omeprazole monotherapy. The results for the efficacy analyses
for these studies are described below. H. pylori eradication was
defined as no positive test (culture or histology) at 4 weeks following
the end of treatment, and two negative tests were required to be
considered eradicated of H. pylori. In the per-protocol analysis, the
following patients were excluded: dropouts, patients with missing H.
pylori tests post-treatment, and patients that were not assessed for H.
pylori eradication because they were found to have an ulcer at the end
of treatment.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori.
Table 7
H. pylori Eradication Rates (Per-Protocol Analysis
at 4 to 6 Weeks)
% of Patients Cured [95% Confidence Interval]
PRILOSEC +
Clarithromycin
PRILOSEC
Clarithromycin
U.S. Studies
Study 4
74 [60, 85] †‡
0 [0, 7]
31 [18, 47]
(n = 53)
(n = 54)
(n = 42)
Study 5
64 [51, 76] †‡
(n = 61)
0 [0, 6]
(n = 59)
39 [24, 55]
(n = 44)
Non U.S. Studies
Study 6
83 [71, 92] ‡
(n = 60)
1 [0, 7]
(n = 74)
N/A
Study 7
74 [64, 83] ‡
1 [0, 6]
N/A
(n = 86)
(n = 90)
†Statistically significantly higher than clarithromycin
monotherapy (p < 0.05)
‡Statistically significantly higher than omeprazole
monotherapy (p < 0.05)
Ulcer healing was not significantly different when clarithromycin was
added to omeprazole therapy compared with omeprazole therapy
alone.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori and reduced duodenal ulcer recurrence.
Table 8
30
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Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status
% of Patients with Ulcer Recurrence
H. pylori eradicated#
H. pylori not eradicated#
U.S. Studies †
6 months post-treatment
Study 4
*35
60
(n = 49)
(n = 88)
Study 5
*8
60
(n = 53)
(n = 106)
Non U.S. Studies ‡
6 months post-treatment
Study 6
*5
46
(n = 43)
(n = 78)
Study 7
*6
43
(n = 53)
(n = 107)
12 months post-treatment
Study 6
*5
68
(n = 39)
(n = 71)
#H. pylori eradication status assessed at same time point as ulcer recurrence
†Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment
arms
‡Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
*(p < 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori
eradicated
14.2 Gastric Ulcer
In a U.S. multicenter, double-blind, study of omeprazole 40 mg once
daily, 20 mg once daily, and placebo in 520 patients with
endoscopically diagnosed gastric ulcer, the following results were
obtained.
Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC
PRILOSEC
20 mg once daily
40 mg once daily
Placebo
(n = 202)
(n = 214)
(n = 104)
Week 4
47.5**
55.6**
30.8
Week 8
48.1
74.8**
82.7**,+
**(p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
+(p < 0.05) PRILOSEC 40 mg versus 20 mg
For the stratified groups of patients with ulcer size less than or equal
to 1 cm, no difference in healing rates between 40 mg and 20 mg was
detected at either 4 or 8 weeks. For patients with ulcer size greater
than 1 cm, 40 mg was significantly more effective than 20 mg at 8
weeks.
In a foreign, multinational, double-blind study of 602 patients with
endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily,
20 mg once daily, and ranitidine 150 mg twice a day were evaluated.
31
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Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
Week 4
Week 8
PRILOSEC
20 mg once daily
(n = 200)
63.5
81.5
PRILOSEC
40 mg once daily
(n = 187)
78.1**,++
91.4**,++
Ranitidine
150 mg twice daily
(n = 199)
56.3
78.4
** (p < 0.01) PRILOSEC 40 mg versus ranitidine
++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
14.3 Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo-controlled study was conducted in Scandinavia to compare
the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4
weeks in the treatment of heartburn and other symptoms in GERD
patients without erosive esophagitis. Results are shown below.
% Successful Symptomatic Outcomea
PRILOSEC
PRILOSEC
Placebo
20 mg a.m.
10 mg a.m.
a.m.
All patients
46*,†
31†
13
(n = 105)
(n = 205)
(n = 199)
Patients with
14
56*,†
36†
confirmed GERD
(n = 59)
(n = 115)
(n = 109)
aDefined as complete resolution of heartburn
*(p < 0.005) versus 10 mg
†(p < 0.005) versus placebo
14.4 Erosive Esophagitis
In a U.S. multicenter double-blind placebo controlled study of 20 mg
or 40 mg of PRILOSEC Delayed-Release Capsules in patients with
symptoms of GERD and endoscopically diagnosed erosive
esophagitis of grade 2 or above, the percentage healing rates (per
protocol) were as follows:
20 mg PRILOSEC
40 mg PRILOSEC
Placebo
Week
(n = 83)
(n = 87)
(n = 43)
4
39**
45**
7
8
14
74**
75**
** (p < 0.01) PRILOSEC versus placebo.
In this study, the 40 mg dose was not superior to the 20 mg dose of
PRILOSEC in the percentage healing rate. Other controlled clinical
trials have also shown that PRILOSEC is effective in severe GERD.
In comparisons with histamine H2-receptor antagonists in patients
with erosive esophagitis, grade 2 or above, PRILOSEC in a dose of
20 mg was significantly more effective than the active controls.
Complete daytime and nighttime heartburn relief occurred
significantly faster (p < 0.01) in patients treated with PRILOSEC than
in those taking placebo or histamine H2- receptor antagonists.
32
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In this and five other controlled GERD studies, significantly more
patients taking 20 mg omeprazole (84%) reported complete relief of
GERD symptoms than patients receiving placebo (12%).
Long Term Maintenance Of Healing of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled
study, two dose regimens of PRILOSEC were studied in patients with
endoscopically confirmed healed esophagitis. Results to determine
maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
PRILOSEC
PRILOSEC
20 mg 3 days
20 mg once daily
per week
Placebo
(n = 138)
(n = 137)
(n = 131)
Percent in
endoscopic
remission at
6 months
*70
34
11
∗(p < 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 20 mg 3 consecutive days per week or
placebo.
In an international multicenter double-blind study, PRILOSEC 20 mg
daily and 10 mg daily were compared with ranitidine 150 mg twice
daily in patients with endoscopically confirmed healed esophagitis.
The table below provides the results of this study for maintenance of
healing of erosive esophagitis.
Life Table Analysis
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
10 mg once daily
150 mg twice daily
(n = 131)
(n = 133)
(n = 128)
Percent in
endoscopic
remission at
12 months
46
*77
‡58
*
(p = 0.01) PRILOSEC 20 mg once daily. versus PRILOSEC 10 mg once daily or
Ranitidine.
‡ (p = 0.03) PRILOSEC 10 mg once daily. versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for
maintenance after healing 20 mg daily of PRILOSEC was effective,
while 10 mg did not demonstrate effectiveness.
14.5 Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory
conditions, such as Zollinger-Ellison (ZE) syndrome with or without
multiple endocrine adenomas, PRILOSEC Delayed-Release Capsules
significantly inhibited gastric acid secretion and controlled associated
symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg
every other day to 360 mg per day maintained basal acid secretion
below 10 mEq/hr in patients without prior gastric surgery, and below
5 mEq/hr in patients with prior gastric surgery.
33
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Initial doses were titrated to the individual patient need, and
adjustments were necessary with time in some patients [See Dosage
and Administration (2)] PRILOSEC was well tolerated at these high
dose levels for prolonged periods (> 5 years in some patients). In
most ZE patients, serum gastrin levels were not modified by
PRILOSEC. However, in some patients serum gastrin increased to
levels greater than those present prior to initiation of omeprazole
therapy. At least 11 patients with ZE syndrome on long-term
treatment with PRILOSEC developed gastric carcinoids. These
findings are believed to be a manifestation of the underlying
condition, which is known to be associated with such tumors, rather
than the result of the administration of PRILOSEC. [See Adverse
Reactions (6)]
14.6 Pediatric GERD
Symptomatic GERD
The effectiveness of PRILOSEC for the treatment of nonerosive
GERD in pediatric patients 1 to 16 years of age is based in part on
data obtained from 125 pediatric patients in two uncontrolled Phase
III studies. [See Use in Specific Populations (8.4)]
The first study enrolled 12 pediatric patients 1 to 2 years of age with a
history of clinically diagnosed GERD. Patients were administered a
single dose of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8
weeks as an open capsule in 8.4% sodium bicarbonate solution.
Seventy-five percent (9/12) of the patients had vomiting/regurgitation
episodes decreased from baseline by at least 50%.
The second study enrolled 113 pediatric patients 2 to 16 years of age
with a history of symptoms suggestive of nonerosive GERD. Patients
were administered a single dose of omeprazole (10 mg or 20 mg,
based on body weight) for 4 weeks either as an intact capsule or as an
open capsule in applesauce. Successful response was defined as no
moderate or severe episodes of either pain-related symptoms or
vomiting/regurgitation during the last 4 days of treatment. Results
showed success rates of 60% (9/15; 10 mg omeprazole) and 59%
(58/98; 20 mg omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive
esophagitis in pediatric patients 1 to 16 years of age required doses
that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were
initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7
mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than
6% of a 24-hour study). After titration, patients remained on
treatment for 3 months. Forty-four percent of the patients were healed
on a dose of 0.7 mg/kg body weight; most of the remaining patients
were healed with 1.4 mg/kg after an additional 3 months’ treatment.
Erosive esophagitis was healed in 51 of 57 (90%) children who
completed the first course of treatment in the healing phase of the
34
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
study. In addition, after 3 months of treatment, 33% of the children
had no overall symptoms, 57% had mild reflux symptoms, and 40%
had less frequent regurgitation/vomiting.
Maintenance of Healing of Erosive Esophagitis
In an uncontrolled, open-label study of maintenance of healing of
erosive esophagitis in 46 pediatric patients, 54% of patients required
half the healing dose. The remaining patients increased the healing
dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire
maintenance period, or returned to half the dose before completion.
Of the 46 patients who entered the maintenance phase, 19 (41%) had
no relapse. In addition, maintenance therapy in erosive esophagitis
patients resulted in 63% of patients having no overall symptoms.
15
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods
for Dilution Antimicrobial Susceptibility Tests for Bacteria That
Grow Aerobically—Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January
2000.
16
HOW SUPPLIED/STORAGE AND HANDLING
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body. They are supplied as follows:
NDC 0186-0606-31 unit of use bottles of 30
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body. They are supplied as follows:
NDC 0186-0742-31 unit of use bottles of 30
NDC 0186-0742-82 bottles of 1000.
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body. They are supplied as follows:
NDC 0186-0743-31 unit of use bottles of 30
NDC 0186-0743-68 bottles of 100
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules. PRILOSEC unit dose packets are supplied as
follows:
35
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 0186-0625-01 unit dose packages of 30: 2.5 mg packets
NDC 0186-0610-01 unit dose packages of 30: 10 mg packets
Storage
Store PRILOSEC Delayed-Release Capsules in a tight container
protected from light and moisture. Store between 15°C and 30°C
(59°F and 86°F).
Store PRILOSEC For Delayed-Release Oral Suspension at 25°C
(77°F); excursions permitted to 15 – 30°C (59 – 86°F). [See USP
Controlled Room Temperature].
17
PATIENT COUNSELING INFORMATION
PRILOSEC should be taken before eating. Patients should be
informed that the PRILOSEC Delayed-Release Capsule should be
swallowed whole.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
36
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
Advise patients to immediately report and seek care for any
cardiovascular or neurological symptoms including palpitations,
dizziness, seizures, and tetany as these may be signs of
hypomagnesemia [see Warnings and Precautions (5.7)].
PRILOSEC is a trademark of the AstraZeneca group of companies.
©AstraZeneca 2011
Manufactured for: AstraZeneca LP, Wilmington, DE 19850
Rev May 2011
FDA-Approved Patient Labeling
PRILOSEC (pry’-lo-sec) (omeprazole) Delayed-Release Capsules
And Delayed-Release Oral Suspension
Read the patient information that comes with PRILOSEC before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
doctor about your medical condition or your treatment.
If you have any questions about PRILOSEC, ask your doctor.
WHAT IS PRILOSEC?
PRILOSEC is a prescription medicine called a proton pump inhibitor
(PPI). PRILOSEC reduces the amount of acid in your stomach.
PRILOSEC is used in adults:
• for up to 4 weeks to treat heartburn and other symptoms that
happen with gastroesophageal reflux disease (GERD).
GERD is a chronic condition (lasts a long time) that occurs
when acid from the stomach backs up into the esophagus
(food pipe) causing symptoms, such as heartburn, or damage
to the lining of the esophagus. Common symptoms include
frequent heartburn that will not go away, a sour or bitter taste
in the mouth, and difficulty swallowing.
• for up to 8 weeks to heal acid-related damage to the lining of
the esophagus (called erosive esophagitis or EE)
37
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• to maintain healing of the esophagus. PRILOSEC has not
been studied for treatment lasting longer than 12 months (1
year)
• for up to 8 weeks for healing stomach ulcers
• for up to 8 weeks for healing ulcers in the first part of the
small bowel (duodenal ulcers)
• to treat patients with a stomach infection (Helicobacter
pylori), along with the antibiotics amoxicillin and
clarithromycin.
• for lowering the amount of stomach acid in people with
certain conditions which cause them to make too much acid,
including those with Zollinger-Ellison Syndrome.
For children and adolescents 1 to 17 years of age, PRILOSEC is used:
• for up to 4 weeks to treat the symptoms of gastroesophageal
reflux disease (GERD).
• for up to 8 weeks to heal acid-related damage to the lining of
the esophagus (called erosive esophagitis or EE)
• to maintain healing of the esophagus
PRILOSEC is not recommended for children under the age of 1 year.
PRILOSEC may help your acid-related symptoms, but you could still
have serious stomach problems. Talk with your doctor.
WHO SHOULD NOT TAKE PRILOSEC?
Do not take PRILOSEC if you:
• are allergic to any of the ingredients in PRILOSEC. See the
end of this leaflet for a complete list of ingredients in
PRILOSEC.
• are allergic to any other Proton Pump Inhibitor (PPI)
medicine.
WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING
PRILOSEC?
Tell your doctor about all your medical conditions, including if you:
• have been told that you have low magnesium levels in your
blood
• have liver problems
• are pregnant or plan to become pregnant. It is not known if
PRILOSEC will harm your unborn baby. Talk to your doctor
if you are pregnant or plan to become pregnant.
• are breastfeeding or planning to breastfeed. You and your
doctor should decide if you will take PRILOSEC or
breastfeed. You should not do both.
Tell your doctor about all of the medicines you take including
prescription and non-prescription drugs, vitamins and herbal
supplements. PRILOSEC may affect how other medicines work, and
38
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
other medicines may affect how PRILOSEC works. Especially tell
your doctor if you take:
• atazanavir (Reyataz)
• nelfinavir (Viracept)
• saquinavir (Fortovase)
• cilostazol (Pletal)
• ketoconazole (Nizoral)
• voriconazole (Vfend)
• ampicillin (Unasyn)
• products that contain iron
• warfarin (Coumadin)
• digoxin (Lanoxin, Lanoxincaps)
• tacrolimus (Prograf)
• diazepam (Valium)
• phenytoin (Dilantin)
• disulfiram (Antabuse)
• clopidogrel (Plavix)
HOW SHOULD I TAKE PRILOSEC?
• Take PRILOSEC exactly as prescribed by your doctor.
• Do not change your dose or stop PRILOSEC without talking
to your doctor.
• Take PRILOSEC at least 1 hour before a meal.
• Swallow PRILOSEC capsules whole. Never chew or crush
PRILOSEC.
• If you have difficulty swallowing PRILOSEC capsules, you
may open the capsule and empty the contents into a
tablespoon of applesauce. Be sure to swallow the applesauce
right away. Do not store it for later use.
• If you forget to take a dose of PRILOSEC, take it as soon as
you remember. If it is almost time for your next dose, do not
take the missed dose. Take the next dose on time. Do not take
a double dose to make up for a missed dose.
• If you take too much PRILOSEC, tell your doctor right away.
• See the “Patient Instructions for Use” at the end of this leaflet
for instructions how to take PRILOSEC Delayed-Release Oral
Suspension, and how to mix and give PRILOSEC For
Delayed-Release Oral Suspension, through a nasogastric tube
or gastric tube.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF PRILOSEC?
• Serious allergic reactions. Tell your doctor if you get any of
the following symptoms with PRILOSEC.
• rash
• face swelling
• throat tightness
• difficulty breathing
39
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Your doctor may stop PRILOSEC if these symptoms happen.
• Low magnesium levels in your body. This problem can be
serious. Low magnesium can happen in some people who take
a proton pump inhibitor medicine for at least 3 months. If low
magnesium levels happen, it is usually after a year of
treatment. You may or may not have symptoms of low
magnesium.
Tell your doctor right away if you have any of these symptoms:
o seizures
o dizziness
o
o abnormal or fast heart beat
o jitteriness
o jerking movements or shaking (tremors)
o muscle weakness
o spasms of the hands and feet
o cramps or muscle aches
o spasm of the voice box
Your doctor may check the level of magnesium in your body before
you start taking PRILOSEC or during treatment if you will be taking
PRILOSEC for a long period of time.
The most common side effects with PRILOSEC in adults and
children include:
• Headache
• Abdominal pain
• Nausea
• Diarrhea
• Vomiting
• Gas
• Respiratory system events
• Fever
People who are taking multiple daily doses of proton pump inhibitor
medicines for a long period of time may have an increased risk of
fractures of the hip, wrist or spine.
Tell your doctor about any side effects that bother you or that do not
go away. These are not all the possible side effects with PRILOSEC.
Talk with your doctor or pharmacist if you have any questions about
side effects. You may report side effects to the FDA at 1-800-FDA
1088.
40
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SHOULD I STORE PRILOSEC?
Store PRILOSEC at room temperature between 59°F to 86°F (15°C to
30°C).
Keep the container of PRILOSEC closed tightly.
Keep PRILOSEC and all medicines out of the reach of children.
GENERAL ADVICE
Medicines are sometimes prescribed for purposes other than those
listed in the Patient Information leaflet. Do not use PRILOSEC for a
condition for which it was not prescribed. Do not give PRILOSEC to
other people, even if they have the same symptoms you have. It may
harm them.
This Patient Information leaflet provides a summary of the most
important information about PRILOSEC. For more information, ask
your doctor. You can ask your doctor or pharmacist for information
that is written for healthcare professionals. For more information, go
to www. astrazeneca-us.com or call toll free 1-800-236-9933.
PATIENT INSTRUCTIONS FOR USE
For instructions on taking Delayed-Release Capsules, please see
“HOW SHOULD I TAKE PRILOSEC?”
Take PRILOSEC Delayed-Release Oral Suspension as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 1 teaspoon (5 mL) of water or empty the contents
of a 10 mg packet into a container with 1 tablespoon (15 mL)
of water
• Stir.
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
If any medicine remains after drinking, add more water, stir, and
drink right away.
PRILOSEC for Delayed-Release Oral Suspension may be given
through a nasogastric tube (NG tube) or gastric tube, as prescribed by
your doctor. Follow the instructions below:
PRILOSEC for Delayed-Release Oral Suspension:
• Add 5 mL of water to a catheter tipped syringe and then add
the contents of a 2.5 mg packet (or 15 mL of water for the 10
mg packet), as instructed by your doctor. Use only a catheter
tipped syringe to give PRILOSEC through a NG tube or
gastric tube.
• Shake the syringe right away and then leave it for 2 to 3
minutes to thicken.
41
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Shake the syringe and give the medicine through the NG or
gastric tube (French size 6 or larger) into the stomach within
30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the NG tube or
gastric tube into the stomach.
WHAT ARE THE INGREDIENTS IN PRILOSEC?
Active ingredient in PRILOSEC Delayed-Release Capsules:
omeprazole
Inactive ingredients in PRILOSEC Delayed-Release Capsules
(including the capsule shells): cellulose, disodium hydrogen
phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate, gelatin-NF, FD&C Blue #1, FD&C Red #40,
D&C Red #28, titanium dioxide, synthetic black iron oxide,
isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7 Calcium
Lake, and, in addition, the 10 mg and 40 mg capsule shells also
contain D&C Yellow #10.
Active ingredient in PRILOSEC for Delayed-Release Oral
Suspension: omeprazole magnesium
Inactive ingredients in PRILOSEC for Delayed-Release Oral
Suspension: glyceryl monostearate, hydroxypropyl cellulose,
hypromellose, magnesium stearate, methacrylic acid copolymer C,
polysorbate, sugar spheres, talc, and triethyl citrate.
Inactive granules in PRILOSEC Delayed-Release Oral
Suspension: citric acid, crospovidone, dextrose, hydroxypropyl
cellulose, iron oxide and xantham gum.
PRILOSEC is a registered trademark of the AstraZeneca group of
companies.
©2010 AstraZeneca Pharmaceuticals LP. All rights reserved.
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
May 2011
42
Reference ID: 2950114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
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|
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|
11,732
|
_______________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRILOSEC safely and effectively. See full prescribing information for
PRILOSEC.
PRILOSEC (omeprazole) Delayed-Release Capsules and PRILOSEC
(omeprazole magnesium) For Delayed-Release Oral Suspension
INITIAL U.S. APPROVAL: 1989
-------------------------RECENT MAJOR CHANGES----------------------------
Warnings and Precautions, Clostridium difficile associated
09/2012
diarrhea (5.3)
Warnings and Precautions, Concomitant use of PRILOSEC
01/2012
with Methotrexate (5.9)
--------------------------INDICATIONS AND USAGE----------------------------
PRILOSEC is a proton pump inhibitor indicated for:
•
Treatment in adults of duodenal ulcer (1.1) and gastric ulcer (1.2)
•
Treatment in adults and children of gastroesophageal reflux disease
(GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4)
The safety and effectiveness of PRILOSEC in pediatric patients <1 year of
age have not been established. (8.4)
-----------------------DOSAGE AND ADMINISTRATION----------------------
Indication
Omeprazole Dose
Frequency
Treatment of Active
Duodenal Ulcer (2.1)
20 mg
Once daily for 4 weeks. Some
patients may require an
additional 4 weeks
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
Triple Therapy:
PRILOSEC
20 mg
Each drug twice daily for 10
Amoxicillin
1000 mg
days
Clarithromycin
500 mg
Dual Therapy:
PRILOSEC
40 mg
Once daily for 14 days
Clarithromycin
500 mg
Three times daily for 14 days
Gastric Ulcer (2.3)
40 mg
Once daily for 4 to 8 weeks
GERD (2.4)
20 mg
Once daily for 4 to 8 weeks
Maintenance of Healing of
Erosive Esophagitis (2.5)
20 mg
Once daily
Pathological Hypersecretory
Conditions (2.6)
60 mg (varies with
individual patient)
Once daily
Pediatric Patients
(1 to 16 years of age) (2.7)
GERD And Maintenance
of Healing of Erosive
Esophagitis
Weight
Dose
5 < 10 kg
5 mg
10< 20 kg 10 mg
> 20 kg
20 mg
Once daily
----------------------DOSAGE FORMS AND STRENGTHS--------------------
•
PRILOSEC Delayed-Release Capsules, 10 mg, 20 mg and 40 mg (3)
•
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg (3)
---------------------------CONTRAINDICATIONS-------------------------------
Known hypersensitivity to any component of the formulation or substituted
benzimidazoles (angioedema and anaphylaxis have occurred) (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
•
Symptomatic response does not preclude the presence of gastric
malignancy (5.1)
•
Atrophic gastritis: has been noted with long-term therapy (5.2)
•
PPI therapy may be associated with increased risk of Clostridium
difficile associated diarrhea. (5.3)
•
Bone Fracture: Long-term and multiple daily dose PPI therapy may be
associated with an increased risk for osteoporosis-related fractures of the
hip, wrist or spine. (5.4)
•
Diminished anti-platelet activity of clopidogrel due to impaired
CYP2C19 function by 80 mg omeprazole (5.5)
•
Hypomagnesemia has been reported rarely with prolonged treatment
with PPIs (5.6)
•
Avoid concomitant use of PRILOSEC with St John’s Wort or rifampin
due to the potential reduction in omeprazole concentrations (5.7, 7.3)
•
Interactions with diagnostic investigations for Neuroendocrine Tumors:
Increases in intragastric pH may result in hypergastrinemia and
enterochromaffin-like cell hyperplasia and increased Choromogranin A
levels which may interfere with diagnostic investigations for
neuroendocrine tumors. (5.8, 12.2)
-------------------------------ADVERSE REACTIONS--------------------------
Adults: Most common adverse reactions in adults (incidence ≥ 2%) are
•
Headache, abdominal pain, nausea, diarrhea, vomiting, and
flatulence (6)
Pediatric patients (1 to 16 years of age):
Safety profile similar to that in adults, except that respiratory system
events and fever were the most frequently reported reactions in pediatric
studies (8.4)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS--------------------------
•
Atazanavir and nelfinavir: PRILOSEC reduces plasma levels of
atazanavir and nelfinavir. Concomitant use is not recommended (7.1)
•
Saquinavir: PRILOSEC increases plasma levels of saquinavir. Monitor
for toxicity and consider dose reduction of saquinavir (7.1)
•
May interfere with drugs for which gastric pH affects bioavailability
(e.g., ketoconazole, iron salts, ampicillin esters, and digoxin). Patients
treated with PRILOSEC and digoxin may need to be monitored for
increases in digoxin toxicity (7.2)
•
Co-administration of clopidogrel with 80 mg omeprazole may reduce the
pharmacological activity of clopidogrel if given concomitantly or if
given 12 hours apart (7)
•
Cilostazol: PRILOSEC increases systemic exposure of cilostazol and
one of its active metabolites. Consider dose reduction of cilostazol.(7.3)
•
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin,
phenytoin, cyclosporine, disulfiram, benzodiazepines): PRILOSEC can
prolong their elimination. Monitor and determine need for dose
adjustments (7.3)
•
Patients treated with proton pump inhibitors and warfarin may need to
be monitored for increases in INR and prothrombin time (7.3)
•
Combined inhibitor of CYP 2C19 and 3A4 (e.g. voriconazole) may raise
omeprazole levels (7.3)
•
Tacrolimus: PRILOSEC may increase serum levels of tacrolimus (7.4)
•
Methotrexate: PRILOSEC may increase serum levels of methotrexate
(7.7)
------------------------USE IN SPECIFIC POPULATIONS----------------------
Patients with hepatic impairment:
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis (12.3)
-----See 17 for Patient Counseling Information and FDA approved
medication guide----
REVISED 09/2012
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
1.2 Gastric Ulcer (adults)
1.3 Treatment of Gastroesophageal Reflux Disease (GERD)
(adults and pediatric patients)
1.4 Maintenance of Healing of Erosive Esophagitis (adults)
1.5 Pathological Hypersecretory Conditions
2
DOSAGE AND ADMINISTRATION
2.1 Short-Term Treatment of Active Duodenal Ulcer
2.2 H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
2.3 Gastric Ulcer
2.4 Gastroesophageal Reflux Disease (GERD)
2.5 Maintenance of Healing of Erosive Esophagitis
2.6 Pathological Hypersecretory Conditions
2.7 Pediatric Patients
2.8 Alternative Administration Options
2.9 Use with clopidogrel
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Concomitant Gastric Malignancy
5.2 Atrophic Gastritis
5.3 Clostridium difficile associated diarrhea
5.4 Bone Fracture
5.5 Diminished anti-platelet activity of clopidogrel due to
impaired CYP2C19 function by omeprazole
5.6 Hypomagnesemia
5.7 Comcomitant Use of PRILOSEC with St John’s Wort or
rifampin
5.8 Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
5.9 Concomitant use of PRILOSEC with Methotrexate
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience with PRILOSEC Monotherapy
6.2 Clinical Trials Experience with PRILOSEC in Combination
Therapy for H. pylori Eradication
6.3 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Interference with Antiretroviral Therapy
7.2 Drugs for Which Gastric pH Can Affect Bioavailability
7.3
Effects on HepaticMetabolism/Cytochrome P-450 Pathways
7.4 Tacrolimus
7.5 Interactions with Investigations of Neuroendocrine Tumors
7.6 Combination Therapy with Clarithromycin
7.7 Methotrexate
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Asian Population
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
14.2 Gastric Ulcer
14.3 Gastroesophageal Reflux Disease (GERD)
14.4 Erosive Esophagitis
14.5 Pathological Hypersecretory Conditions
14.6 Pediatric GERD
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1
Duodenal Ulcer (adults)
PRILOSEC is indicated for short-term treatment of active duodenal
ulcer in adults. Most patients heal within four weeks. Some patients
may require an additional four weeks of therapy.
PRILOSEC in combination with clarithromycin and amoxicillin, is
indicated for treatment of patients with H. pylori infection and
duodenal ulcer disease (active or up to 1-year history) to eradicate H.
pylori in adults.
PRILOSEC in combination with clarithromycin is indicated for
treatment of patients with H. pylori infection and duodenal ulcer
disease to eradicate H. pylori in adults.
Eradication of H. pylori has been shown to reduce the risk of
duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage
and Administration (2)].
Among patients who fail therapy, PRILOSEC with clarithromycin is
more likely to be associated with the development of clarithromycin
resistance as compared with triple therapy. In patients who fail
therapy, susceptibility testing should be done. If resistance to
clarithromycin is demonstrated or susceptibility testing is not
possible, alternative antimicrobial therapy should be instituted. [See
Microbiology section (12.4)], and the clarithromycin package insert,
Microbiology section.)
1.2
Gastric Ulcer (adults)
PRILOSEC is indicated for short-term treatment (4-8 weeks) of active
benign gastric ulcer in adults. [See Clinical Studies (14.2)]
1.3
Treatment of Gastroesophageal Reflux Disease
(GERD) (adults and pediatric patients)
Symptomatic GERD
PRILOSEC is indicated for the treatment of heartburn and other
symptoms associated with GERD in pediatric patients and adults.
Erosive Esophagitis
PRILOSEC is indicated for the short-term treatment (4-8 weeks) of
erosive esophagitis that has been diagnosed by endoscopy in pediatric
patients and adults. [See Clinical Studies (14.4)]
3
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of PRILOSEC used for longer than 8 weeks in these
patients has not been established. If a patient does not respond to 8
weeks of treatment, an additional 4 weeks of treatment may be given.
If there is recurrence of erosive esophagitis or GERD symptoms (eg,
heartburn), additional 4-8 week courses of omeprazole may be
considered.
1.4
Maintenance of Healing of Erosive Esophagitis
(adults and pediatric patients)
PRILOSEC is indicated to maintain healing of erosive esophagitis in
pediatric patients and adults.
Controlled studies do not extend beyond 12 months. [See Clinical
Studies (14.4)]
1.5
Pathological Hypersecretory Conditions (adults)
PRILOSEC is indicated for the long-term treatment of pathological
hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple
endocrine adenomas and systemic mastocytosis) in adults.
2
DOSAGE AND ADMINISTRATION
PRILOSEC Delayed-Release Capsules should be taken before eating.
In the clinical trials, antacids were used concomitantly with
PRILOSEC.
Patients should be informed that the PRILOSEC Delayed-Release
Capsule should be swallowed whole.
For patients unable to swallow an intact capsule, alternative
administration options are available [See Dosage and Administration
(2.8)].
2.1
Short-Term Treatment of Active Duodenal Ulcer
The recommended adult oral dose of PRILOSEC is 20 mg once daily.
Most patients heal within four weeks. Some patients may require an
additional four weeks of therapy.
2.2
H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin) — The
recommended adult oral regimen is PRILOSEC 20 mg plus
clarithromycin 500 mg plus amoxicillin 1000 mg each given twice
daily for 10 days. In patients with an ulcer present at the time of
initiation of therapy, an additional 18 days of PRILOSEC 20 mg once
daily is recommended for ulcer healing and symptom relief.
Dual Therapy (PRILOSEC/clarithromycin) — The recommended
adult oral regimen is PRILOSEC 40 mg once daily plus
clarithromycin 500 mg three times daily for 14 days. In patients with
an ulcer present at the time of initiation of therapy, an additional 14
4
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
days of PRILOSEC 20 mg once daily is recommended for ulcer
healing and symptom relief.
2.3
Gastric Ulcer
The recommended adult oral dose is 40 mg once daily for 4-8 weeks.
2.4
Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients with
symptomatic GERD and no esophageal lesions is 20 mg daily for up
to 4 weeks. The recommended adult oral dose for the treatment of
patients with erosive esophagitis and accompanying symptoms due to
GERD is 20 mg daily for 4 to 8 weeks.
2.5
Maintenance of Healing of Erosive Esophagitis
The recommended adult oral dose is 20 mg daily. [See Clinical
Studies (14.4)]
2.6
Pathological Hypersecretory Conditions
The dosage of PRILOSEC in patients with pathological
hypersecretory conditions varies with the individual patient. The
recommended adult oral starting dose is 60 mg once daily. Doses
should be adjusted to individual patient needs and should continue for
as long as clinically indicated. Doses up to 120 mg three times daily
have been administered. Daily dosages of greater than 80 mg should
be administered in divided doses. Some patients with Zollinger-
Ellison syndrome have been treated continuously with PRILOSEC for
more than 5 years.
2.7
Pediatric Patients
For the treatment of GERD and maintenance of healing of erosive
esophagitis, the recommended daily dose for pediatric patients 1 to
16 years of age is as follows:
Patient Weight
Omeprazole Daily Dose
5 < 10 kg
5 mg
10 < 20 kg
10 mg
> 20 kg
20 mg
On a per kg basis, the doses of omeprazole required to heal erosive
esophagitis in pediatric patients are greater than those for adults.
Alternative administrative options can be used for pediatric patients
unable to swallow an intact capsule [See Dosage and Administration
(2.8)].
2.8
Alternative Administration Options
PRILOSEC is available as a delayed-release capsule or as a delayed-
release oral suspension.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
5
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
2.9
Use with clopidogrel
Avoid concomitant use of clopidogrel and omeprazole. Co
administration of clopidogrel with 80 mg omeprazole, a proton pump
inhibitor that is an inhibitor of CYP2C19, reduces the
pharmacological activity of clopidogrel if given concomitantly or if
given 12 hours apart [see Warnings and Precautions (5.4) and Drug
Interactions (7.3)].
3
DOSAGE FORMS AND STRENGTHS
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body.
6
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body.
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body.
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules.
4
CONTRAINDICATIONS
PRILOSEC Delayed-Release Capsules are contraindicated in patients
with known hypersensitivity to substituted benzimidazoles or to any
component of the formulation. Hypersensitivity reactions may include
anaphylaxis,
anaphylactic
shock,
angioedema,
bronchospasm,
interstitial nephritis, and urticaria [See Adverse Reactions (6)].
For information about contraindications of antibacterial agents
(clarithromycin and amoxicillin) indicated in combination with
PRILOSEC, refer to the CONTRAINDICATIONS section of their
package inserts.
5
WARNINGS AND PRECAUTIONS
5.1
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude
the presence of gastric malignancy.
5.2
Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus
biopsies from patients treated long-term with omeprazole.
5.3
Clostridium difficile associated diarrhea
Published observational studies suggest that PPI therapy like
PRILOSEC may be associated with an increased risk of Clostridium
difficile associated diarrhea, especially in hospitalized patients. This
diagnosis should be considered for diarrhea that does not improve
[see Adverse Reactions (6.2)].
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated.
Clostridium diffficile associated diarrhea (CDAD) has been reported
with use of nearly all antibacterial agents. For more information
specific to antibacterial agents (clarithromycin and amoxicillin)
7
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
indicated for use in combination with PRILOSEC, refer to
WARNINGS and PRECAUTIONS sections of those package inserts.
5.4
Bone Fracture
Several published observational studies suggest that proton pump
inhibitor (PPI) therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as
multiple daily doses, and long-term PPI therapy (a year or longer).
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated. Patients at risk for
osteoporosis-related fractures should be managed according to
established treatment guidelines. [see Dosage and Administration (2)
and Adverse Reactions (6.3)]
5.5
Diminished Anti-platelet Activity of clopidogrel due
to Impaired CYP2C19 Function by Omeprazole
Clopidogrel is a prodrug. Inhibition of platelet aggregation by
clopidogrel is entirely due to an active metabolite. The metabolism of
clopidogrel to its active metabolite can be impaired by use with
concomitant medications, such as omeprazole, that interfere with
CYP2C19 activity. Avoid concomitant use of clopidogrel and
omeprazole. Co-administration of clopidogrel with 80 mg
omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19,
reduces the pharmacological activity of clopidogrel if given
concomitantly or if given 12 hours apart [see Drug Interactions (7)].
5.6
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported
rarely in patients treated with PPIs for at least three months, in most
cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of
hypomagnesemia required magnesium replacement and
discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs
with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), health care professionals may
consider monitoring magnesium levels prior to initiation of PPI
treatment and periodically. [See Adverse Reactions (6.3)]
5.7
Concomitant use of PRILOSEC with St John’s Wort
or rifampin
Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort
or rifampin) can substantially decrease omeprazole concentrations.
[See Drug Interactions (7.3)] Avoid concomitant use of PRILOSEC
with St John’s Wort or rifampin.
8
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.8
Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
Serum chromogranin A (CgA) levels increase secondary to drug-
induced decreases in gastric acidity. The increased CgA level may
cause false positive results in diagnostic investigations for
neuroendocrine tumors. Providers should temporarily stop
omeprazole treatment before assessing CgA levels and consider
repeating the test if initial CgA levels are high. If serial tests are
performed (e.g. for monitoring), the same commercial laboratory
should be used for testing, as reference ranges between tests may
vary.
5.9
Concomitant use of PRILOSEC with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate
(primarily at high dose; see methotrexate prescribing information)
may elevate and prolong serum levels of methotrexate and/or its
metabolite, possibly leading to methotrexate toxicities. In high-dose
methotrexate administration a temporary withdrawal of the PPI may
be considered in some patients. [see Drug Interactions (7. 7)]
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience with PRILOSEC
Monotherapy
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The safety data described below reflects exposure to PRILOSEC
Delayed-Release Capsules in 3096 patients from worldwide clinical
trials (465 patients from US studies and 2,631 patients from
international studies). Indications clinically studied in US trials
included duodenal ulcer, resistant ulcer, and Zollinger-Ellison
syndrome. The international clinical trials were double blind and
open-label in design. The most common adverse reactions reported
(i.e., with an incidence rate ≥ 2%) from PRILOSEC-treated patients
enrolled in these studies included headache (6.9%), abdominal pain
(5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and
flatulence (2.7%).
Additional adverse reactions that were reported with an incidence
≥1% included acid regurgitation (1.9%), upper respiratory infection
(1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia
(1.3%), back pain (1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age
was similar to that in patients 65 years of age or less.
The clinical trial safety profile in pediatric patients who received
PRILOSEC Delayed-Release Capsules was similar to that in adult
9
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients. Unique to the pediatric population, however, adverse
reactions of the respiratory system were most frequently reported in
both the 1 to <2 and 2 to 16 year age groups (75.0% and 18.5%,
respectively). Similarly, fever was frequently reported in the 1 to 2
year age group (33.0%), and accidental injuries were reported
frequently in the 2 to 16 year age group (3.8%).[See Use in Specific
Populations (8.4)]
6.2
Clinical Trials Experience with PRILOSEC in
Combination Therapy for H. pylori Eradication
In clinical trials using either dual therapy with PRILOSEC and
clarithromycin, or triple therapy with PRILOSEC, clarithromycin,
and amoxicillin, no adverse reactions unique to these drug
combinations were observed. Adverse reactions observed were
limited to those previously reported with omeprazole, clarithromycin,
or amoxicillin alone.
Dual Therapy (PRILOSEC/clarithromycin)
Adverse reactions observed in controlled clinical trials using
combination therapy with PRILOSEC and clarithromycin (n = 346)
that differed from those previously described for PRILOSEC alone
were taste perversion (15%), tongue discoloration (2%), rhinitis (2%),
pharyngitis (1%) and flu-syndrome (1%). (For more information on
clarithromycin, refer to the clarithromycin prescribing information,
Adverse Reactions section).
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)
The most frequent adverse reactions observed in clinical trials using
combination therapy with PRILOSEC, clarithromycin, and
amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%),
and headache (7%). None of these occurred at a higher frequency
than that reported by patients taking antimicrobial agents alone. (For
more information on clarithromycin or amoxicillin, refer to the
respective prescribing information, Adverse Reactions sections).
6.3
Post-marketing Experience
The following adverse reactions have been identified during post-
approval use of PRILOSEC Delayed-Release Capsules. Because
these reactions are voluntarily reported from a population of uncertain
size, it is not always possible to reliably estimate their actual
frequency or establish a causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions including anaphylaxis,
anaphylactic shock, angioedema, bronchospasm, interstitial nephritis,
urticaria, (see also Skin below); fever; pain; fatigue; malaise;
Cardiovascular: Chest pain or angina, tachycardia, bradycardia,
palpitations, elevated blood pressure, peripheral edema
Endocrine: Gynecomastia
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon,
fecal discoloration, esophageal candidiasis, mucosal atrophy of the
10
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
tongue, stomatitis, abdominal swelling, dry mouth, microscopic
colitis. During treatment with omeprazole, gastric fundic gland
polyps have been noted rarely. These polyps are benign and appear to
be reversible when treatment is discontinued.
Gastroduodenal carcinoids have been reported in patients with ZE
syndrome on long-term treatment with PRILOSEC. This finding is
believed to be a manifestation of the underlying condition, which is
known to be associated with such tumors.
Hepatic: Liver disease including hepatic failure (some fatal), liver
necrosis (some fatal), hepatic encephalopathy hepatocellular disease,
cholestatic disease, mixed hepatitis, jaundice, and elevations of liver
function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
Infections and Infestations: Clostridium difficile associated diarrhea
Metabolism and Nutritional disorders: Hypoglycemia,
hypomagnesemia, hyponatremia, weight gain
Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint
pain, leg pain, bone fracture
Nervous System/Psychiatric: Psychiatric and sleep disturbances
including depression, agitation, aggression, hallucinations, confusion,
insomnia, nervousness, apathy, somnolence, anxiety, and dream
abnormalities; tremors, paresthesia; vertigo
Respiratory: Epistaxis, pharyngeal pain
Skin: Severe generalized skin reactions including toxic epidermal
necrolysis (some fatal), Stevens-Johnson syndrome, and erythema
multiforme; photosensitivity; urticaria; rash; skin inflammation;
pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis
Special Senses: Tinnitus, taste perversion
Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic
neuritis, dry eye syndrome, ocular irritation, blurred vision, double
vision
Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated
serum creatinine, microscopic pyuria, urinary tract infection,
glycosuria, urinary frequency, testicular pain
Hematologic: Agranulocytosis (some fatal), hemolytic anemia,
pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia,
leucocytosis
7
DRUG INTERACTIONS
7.1
Interference with Antiretroviral Therapy
Concomitant use of atazanavir and nelfinavir with proton pump
inhibitors is not recommended. Co-administration of atazanavir with
proton pump inhibitors is expected to substantially decrease
atazanavir plasma concentrations and may result in a loss of
therapeutic effect and the development of drug resistance. Co
administration of saquinavir with proton pump inhibitors is expected
to increase saquinavir concentrations, which may increase toxicity
and require dose reduction.
Omeprazole has been reported to interact with some antiretroviral
drugs. The clinical importance and the mechanisms behind these
11
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
interactions are not always known. Increased gastric pH during
omeprazole treatment may change the absorption of the antiretroviral
drug. Other possible interaction mechanisms are via CYP 2C19.
Reduced concentrations of atazanavir and nelfinavir
For some antiretroviral drugs, such as atazanavir and nelfinavir,
decreased serum levels have been reported when given together with
omeprazole. Following multiple doses of nelfinavir (1250 mg, twice
daily) and omeprazole (40 mg daily), AUC was decreased by 36%
and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%
respectively for nelfinavir and M8. Following multiple doses of
atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before
atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by
95%. Concomitant administration with omeprazole and drugs such as
atazanavir and nelfinavir is therefore not recommended.
Increased concentrations of saquinavir
For other antiretroviral drugs, such as saquinavir, elevated serum
levels have been reported, with an increase in AUC by 82%, in Cmax
by 75%, and in Cmin by 106%, following multiple dosing of
saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with
omeprazole 40 mg daily co-administered days 11 to 15. Therefore,
clinical and laboratory monitoring for saquinavir toxicity is
recommended during concurrent use with PRILOSEC. Dose
reduction of saquinavir should be considered from the safety
perspective for individual patients.
There are also some antiretroviral drugs of which unchanged serum
levels have been reported when given with omeprazole.
7.2
Drugs for Which Gastric pH Can Affect
Bioavailability
Because of its profound and long lasting inhibition of gastric acid
secretion, it is theoretically possible that omeprazole may interfere
with absorption of drugs where gastric pH is an important
determinant of their bioavailability. Like with other drugs that
decrease the intragastric acidity, the absorption of drugs such as
ketoconazole, ampicillin esters, iron salts and erlotinib can decrease,
while the absorption of drugs such as digoxin can increase during
treatment with omeprazole. Concomitant treatment with omeprazole
(20 mg daily) and digoxin in healthy subjects increased the
bioavailability of digoxin by 10% (30% in two subjects). Therefore,
patients may need to be monitored when digoxin is taken
concomitantly with omeprazole. In the clinical trials, antacids were
used concomitantly with the administration of PRILOSEC.
12
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.3
Effects on Hepatic Metabolism/Cytochrome P-450
Pathways
Omeprazole can prolong the elimination of diazepam, warfarin and
phenytoin, drugs that are metabolized by oxidation in the liver. There
have been reports of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including omeprazole, and warfarin
concomitantly. Increases in INR and prothrombin time may lead to
abnormal bleeding and even death. Patients treated with proton pump
inhibitors and warfarin may need to be monitored for increases in
INR and prothrombin time.
Although in normal subjects no interaction with theophylline or
propranolol was found, there have been clinical reports of interaction
with other drugs metabolized via the cytochrome P450 system (e.g.,
cyclosporine, disulfiram, benzodiazepines). Patients should be
monitored to determine if it is necessary to adjust the dosage of these
drugs when taken concomitantly with PRILOSEC.
Concomitant administration of omeprazole and voriconazole (a
combined inhibitor of CYP2C19 and CYP3A4) resulted in more than
doubling of the omeprazole exposure. Dose adjustment of omeprazole
is not normally required. However, in patients with Zollinger-Ellison
syndrome, who may require higher doses up to 240 mg/day, dose
adjustment may be considered. When voriconazole (400 mg Q12h x 1
day, then 200 mg x 6 days) was given with omeprazole (40 mg once
daily x 7 days) to healthy subjects, it significantly increased the
steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times
(90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as
compared to when omeprazole was given without voriconazole.
Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in
doses of 40 mg daily for one week to 20 healthy subjects in cross
over study, increased Cmax and AUC of cilostazol by 18% and 26%
respectively. Cmax and AUC of one of its active metabolites, 3,4
dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were
increased by 29% and 69% respectively. Co-administration of
cilostazol with omeprazole is expected to increase concentrations of
cilostazol and its above mentioned active metabolite. Therefore a
dose reduction of cilostazol from 100 mg twice daily to 50 mg twice
daily should be considered.
Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin)
may lead to decreased omeprazole serum levels. In a cross-over study
in 12 healthy male subjects, St John’s wort (300 mg three times daily
for 14 days), an inducer of CYP3A4, decreased the systemic exposure
of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC
decreased by 37.5% and 37.9%, respectively) and extensive
metabolisers (Cmax and AUC decreased by 49.6% and 43.9%,
respectively). Avoid concomitant use of St. John’s Wort or rifampin
with omeprazole.
13
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is
metabolized to its active metabolite in part by CYP2C19.
Concomitant use of omeprazole 80 mg results in reduced plasma
concentrations of the active metabolite of clopidogrel and a reduction
in platelet inhibition [see Warnings and Precautions (5.5)].
In a crossover clinical study, 72 healthy subjects were administered
clopidogrel (300 mg loading dose followed by 75 mg per day) alone
and with omeprazole (80 mg at the same time as clopidogrel) for 5
days. The exposure to the active metabolite of clopidogrel was
decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and
omeprazole were administered together. The active metabolite of
clopidogrel selectively and irreversibly inhibits the binding of
adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thereby
inhibiting platelet aggregation. The mean inhibition of platelet
aggregation at 5 mcM ADP was diminished by 39% (Day 1) and 21%
(Day 5) when clopidogrel and omeprazole were administered
together.
In another study, 72 healthy subjects were given the same doses of
clopidogrel and 80 mg omeprazole but the drugs were administered
12 hours apart; the results were similar, indicating that administering
clopidogrel and omeprazole at different times does not prevent their
interaction [see Warnings and Precautions (5.5)].
There are no adequate combination studies of a lower dose of
omeprazole or a higher dose of clopidogrel in comparison with the
approved dose of clopidogrel.
7.4
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may
increase the serum levels of tacrolimus.
7.5
Interactions With Investigations of Neuroendocrine
Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin
like cell hyperplasia and increased Chromogranin A levels which may
interfere with investigations for neuroendocrine tumors. [see
Warnings and Precautions (5.8) and Clinical Pharmacology (12)].
7.6
Combination Therapy with Clarithromycin
Concomitant administration of clarithromycin with other drugs can
lead to serious adverse reactions due to drug interactions [see
Warnings and Precautions in prescribing information for
clarithromycin]. Because of these drug interactions, clarithromycin is
contraindicated for co-administration with certain drugs [see
Contraindications in prescribing information for clarithromycin].
14
Reference ID: 3196017
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7. 7
Methotrexate
Case reports, published population pharmacokinetic studies, and
retrospective analyses suggest that concomitant administration of
PPIs and methotrexate (primarily at high dose; see methotrexate
prescribing information) may elevate and prolong serum levels of
methotrexate and/or its metabolite hydroxymethotrexate. However,
no formal drug interaction studies of methotrexate with PPIs have
been conducted [see Warnings and Precautions (5.9)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Reproductive studies in rats and rabbits with omeprazole and multiple
cohort studies in pregnant women with omeprazole use during the
first trimester do not show an increased risk of congenital anomalies
or adverse pregnancy outcomes. There are no adequate and
well-controlled studies on the use of omeprazole in pregnant women.
Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if
clearly needed. The vast majority of reported experience with
omeprazole during human pregnancy is first trimester exposure and
the duration of use is rarely specified, e.g., intermittent vs. chronic.
An expert review of published data on experiences with omeprazole
use during pregnancy by TERIS – the Teratogen Information System
– concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (the quantity and quality of data
were assessed as fair).
Three epidemiological studies compared the frequency of congenital
abnormalities among infants born to women who used omeprazole
during pregnancy with the frequency of abnormalities among infants
of women exposed to H2-receptor antagonists or other controls. A
population-based prospective cohort epidemiological study from the
Swedish Medical Birth Registry, covering approximately 99% of
pregnancies, reported on 955 infants (824 exposed during the first
trimester with 39 of these exposed beyond first trimester, and 131
exposed after the first trimester) whose mothers used omeprazole
during pregnancy. In utero exposure to omeprazole was not
associated with increased risk of any malformation (odds ratio 0.82,
95% CI 0.50-1.34), low birth weight or low Apgar score. The
number of infants born with ventricular septal defects and the number
of stillborn infants was slightly higher in the omeprazole-exposed
infants than the expected number in the normal population. The
author concluded that both effects may be random.
A retrospective cohort study reported on 689 pregnant women
exposed to either H2-blockers or omeprazole in the first trimester (134
exposed to omeprazole). The overall malformation rate was 4.4%
(95% CI 3.6-5.3) and the malformation rate for first trimester
exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk
15
Reference ID: 3196017
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of malformations associated with first trimester exposure to
omeprazole compared with non-exposed women was 0.9
(95% CI 0.3-2.2). The study could effectively rule out a relative risk
greater than 2.5 for all malformations. Rates of preterm delivery or
growth retardation did not differ between the groups.
A controlled prospective observational study followed 113 women
exposed to omeprazole during pregnancy (89% first trimester
exposures). The reported rates of major congenital malformations
was 4% for the omeprazole group, 2% for controls exposed to non
teratogens, and 2.8% in disease-paired controls (background
incidence of major malformations 1-5%). Rates of spontaneous and
elective abortions, preterm deliveries, gestational age at delivery, and
mean birth weight did not differ between the groups. The sample size
in this study has 80% power to detect a 5-fold increase in the rate of
major malformation.
Several studies have reported no apparent adverse short-term effects
on the infant when single dose oral or intravenous omeprazole was
administered to over 200 pregnant women as premedication for
cesarean section under general anesthesia.
Reproductive studies conducted with omeprazole on rats at oral doses
up to 56 times the human dose and in rabbits at doses up to 56 times
the human dose did not show any evidence of teratogenicity. In
pregnant rabbits, omeprazole at doses about 5.5 to 56 times the
human dose produced dose-related increases in embryo-lethality, fetal
resorptions, and pregnancy loss. In rats treated with omeprazole at
doses about 5.6 to 56 times the human dose, dose-related
embryo/fetal toxicity and postnatal developmental toxicity occurred
in offspring. [See Animal Toxicology and/or Pharmacology (13.2)].
8.3
Nursing Mothers
Omeprazole concentrations have been measured in breast milk of a
woman following oral administration of 20 mg. The peak
concentration of omeprazole in breast milk was less than 7% of the
peak serum concentration. This concentration would correspond to
0.004 mg of omeprazole in 200 mL of milk. Because omeprazole is
excreted in human milk, because of the potential for serious adverse
reactions in nursing infants from omeprazole, and because of the
potential for tumorigenicity shown for omeprazole in rat
carcinogenicity studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
8.4
Pediatric Use
Use of PRILOSEC in pediatric and adolescent patients 1 to 16 years
of age for the treatment of GERD is supported by a) extrapolation of
results, already included in the currently approved labeling, from
adequate and well-controlled studies that supported the approval of
16
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PRILOSEC for adults, and b) safety and pharmacokinetic studies
performed in pediatric and adolescent patients. [See Clinical
Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic
information (12.3) and Dosage and Administration (2), Adverse
Reactions (6.1) and Clinical Studies, (14.6)]. The safety and
effectiveness of PRILOSEC for the treatment of GERD in patients <1
year of age have not been established. The safety and effectiveness of
PRILOSEC for other pediatric uses have not been established.
8.5
Geriatric Use
Omeprazole was administered to over 2000 elderly individuals (≥ 65
years of age) in clinical trials in the U.S. and Europe. There were no
differences in safety and effectiveness between the elderly and
younger subjects. Other reported clinical experience has not
identified differences in response between the elderly and younger
subjects, but greater sensitivity of some older individuals cannot be
ruled out.
Pharmacokinetic studies have shown the elimination rate was
somewhat decreased in the elderly and bioavailability was increased.
The plasma clearance of omeprazole was 250 mL/min (about half that
of young volunteers) and its plasma half-life averaged one hour, about
twice that of young healthy volunteers. However, no dosage
adjustment is necessary in the elderly. [See Clinical Pharmacology
(12.3)]
8.6
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
8.7
Renal Impairment
No dosage reduction is necessary. [See Clinical Pharmacology
(12.3)]
8.8
Asian Population
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
10
OVERDOSAGE
Reports have been received of overdosage with omeprazole in
humans. Doses ranged up to 2400 mg (120 times the usual
recommended clinical dose). Manifestations were variable, but
included confusion, drowsiness, blurred vision, tachycardia, nausea,
vomiting, diaphoresis, flushing, headache, dry mouth, and other
adverse reactions similar to those seen in normal clinical experience.
[See Adverse Reactions (6)] Symptoms were transient, and no serious
clinical outcome has been reported when PRILOSEC was taken
alone. No specific antidote for omeprazole overdosage is known.
Omeprazole is extensively protein bound and is, therefore, not readily
17
Reference ID: 3196017
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dialyzable. In the event of overdosage, treatment should be
symptomatic and supportive.
As with the management of any overdose, the possibility of multiple
drug ingestion should be considered. For current information on
treatment of any drug overdose, contact a Poison Control Center at 1
800-222-1222.
Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were
lethal to mice, rats, and dogs, respectively. Animals given these doses
showed sedation, ptosis, tremors, convulsions, and decreased activity,
body temperature, and respiratory rate and increased depth of
respiration.
11
DESCRIPTION
The active ingredient in PRILOSEC (omeprazole) Delayed-Release
Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy
3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a
compound that inhibits gastric acid secretion. Its empirical formula is
C17H19N3O3S, with a molecular weight of 345.42. The structural
formula is: chemical structure
Omeprazole is a white to off-white crystalline powder that melts with
decomposition at about 155°C. It is a weak base, freely soluble in
ethanol and methanol, and slightly soluble in acetone and isopropanol
and very slightly soluble in water. The stability of omeprazole is a
function of pH; it is rapidly degraded in acid media, but has
acceptable stability under alkaline conditions.
The active ingredient in PRILOSEC (omeprazole magnesium) for
Delayed Release Oral Suspension, is 5-Methoxy-2-[[(4-methoxy-3,5
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium
salt (2:1)
Omeprazole magnesium is a white to off white powder with a melting
point with degradation at 200°C. The salt is slightly soluble (0.25
mg/mL) in water at 25°C, and it is soluble in methanol. The half-life
is highly pH dependent.
The empirical formula for omeprazole magnesium is (C17H18N3O3S)2
Mg, the molecular weight is 713.12 and the structural formula is:
18
Reference ID: 3196017
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chemical structure
PRILOSEC is supplied as delayed-release capsules for oral
administration. Each delayed-release capsule contains either 10 mg,
20 mg or 40 mg of omeprazole in the form of enteric-coated granules
with the following inactive ingredients: cellulose, disodium hydrogen
phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate and other ingredients. The capsule shells have
the following inactive ingredients: gelatin-NF, FD&C Blue #1,
FD&C Red #40, D&C Red #28, titanium dioxide, synthetic black iron
oxide, isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7
Calcium Lake, and, in addition, the 10 mg and 40 mg capsule shells
also contain D&C Yellow #10.
Each packet of PRILOSEC For Delayed-Release Oral Suspension
contains either 2.8 mg or 11.2 mg of omeprazole magnesium
(equivalent to 2.5 mg or 10 mg of omeprazole), in the form of enteric
coated granules with the following inactive ingredients: glyceryl
monostearate, hydroxypropyl cellulose, hypromellose, magnesium
stearate, methacrylic acid copolymer C, polysorbate, sugar spheres,
talc, and triethyl citrate, and also inactive granules. The inactive
granules are composed of the following ingredients: citric acid,
crospovidone, dextrose, hydroxypropyl cellulose, iron oxide and
xantham gum. The omeprazole granules and inactive granules are
constituted with water to form a suspension and are given by oral,
nasogastric or direct gastric administration.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Omeprazole belongs to a class of antisecretory compounds, the
substituted benzimidazoles, that suppress gastric acid secretion by
specific inhibition of the H+/K+ ATPase enzyme system at the
secretory surface of the gastric parietal cell. Because this enzyme
system is regarded as the acid (proton) pump within the gastric
mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect
is dose-related and leads to inhibition of both basal and stimulated
acid secretion irrespective of the stimulus. Animal studies indicate
that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
12.2 Pharmacodynamics
Antisecretory Activity
After oral administration, the onset of the antisecretory effect of
omeprazole occurs within one hour, with the maximum effect
19
Reference ID: 3196017
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occurring within two hours. Inhibition of secretion is about 50% of
maximum at 24 hours and the duration of inhibition lasts up to 72
hours. The antisecretory effect thus lasts far longer than would be
expected from the very short (less than one hour) plasma half-life,
apparently due to prolonged binding to the parietal H+/K+ ATPase
enzyme. When the drug is discontinued, secretory activity returns
gradually, over 3 to 5 days. The inhibitory effect of omeprazole on
acid secretion increases with repeated once-daily dosing, reaching a
plateau after four days.
Results from numerous studies of the antisecretory effect of multiple
doses of 20 mg and 40 mg of omeprazole in normal volunteers and
patients are shown below. The “max” value represents determinations
at a time of maximum effect (2-6 hours after dosing), while “min”
values are those 24 hours after the last dose of omeprazole.
Table 1
Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole
After Multiple Daily Dosing
Omeprazole
Omeprazole
Parameter
20 mg
40 mg
% Decrease in Basal Acid
Output
Max
78*
Min
58-80
Max
94*
Min
80-93
% Decrease in Peak Acid
Output
79*
50-59
88*
62-68
% Decrease in 24-hr.
Intragastric Acidity
80-97
92-94
*Single Studies
Single daily oral doses of omeprazole ranging from a dose of 10 mg
to 40 mg have produced 100% inhibition of 24-hour intragastric
acidity in some patients.
Serum Gastrin Effects
In studies involving more than 200 patients, serum gastrin levels
increased during the first 1 to 2 weeks of once-daily administration of
therapeutic doses of omeprazole in parallel with inhibition of acid
secretion. No further increase in serum gastrin occurred with
continued treatment. In comparison with histamine H2-receptor
antagonists, the median increases produced by 20 mg doses of
omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase).
Gastrin values returned to pretreatment levels, usually within 1 to 2
weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and
increased serum Chromogranin A (CgA) levels. The increased CgA
levels may cause false positive results in diagnostic investigations for
neuroendocrine tumors.
Enterochromaffin-like (ECL) Cell Effects
20
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Human gastric biopsy specimens have been obtained from more than
3000 patients treated with omeprazole in long-term clinical trials. The
incidence of ECL cell hyperplasia in these studies increased with
time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia
has been found in these patients. [See Clinical Pharmacology (12)]
However, these studies are of insufficient duration and size to rule out
the possible influence of long-term administration of omeprazole on
the development of any premalignant or malignant conditions.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and
respiratory systems have not been found to date. Omeprazole, given
in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid
function, carbohydrate metabolism, or circulating levels of
parathyroid hormone, cortisol, estradiol, testosterone, prolactin,
cholecystokinin or secretin.
No effect on gastric emptying of the solid and liquid components of a
test meal was demonstrated after a single dose of omeprazole 90 mg.
In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had
no effect on intrinsic factor secretion. No systematic dose-dependent
effect has been observed on basal or stimulated pepsin output in
humans.
However, when intragastric pH is maintained at 4.0 or above, basal
pepsin output is low, and pepsin activity is decreased.
As do other agents that elevate intragastric pH, omeprazole
administered for 14 days in healthy subjects produced a significant
increase in the intragastric concentrations of viable bacteria. The
pattern of the bacterial species was unchanged from that commonly
found in saliva. All changes resolved within three days of stopping
treatment.
The course of Barrett’s esophagus in 106 patients was evaluated in a
U.S. double-blind controlled study of PRILOSEC 40 mg twice daily
for 12 months followed by 20 mg twice daily for 12 months or
ranitidine 300 mg twice daily for 24 months. No clinically significant
impact on Barrett’s mucosa by antisecretory therapy was observed.
Although neosquamous epithelium developed during antisecretory
therapy, complete elimination of Barrett’s mucosa was not achieved.
No significant difference was observed between treatment groups in
development of dysplasia in Barrett’s mucosa and no patient
developed esophageal carcinoma during treatment. No significant
differences between treatment groups were observed in development
of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal
metaplasia, or colon polyps exceeding 3 mm in diameter [See Clinical
Pharmacology (12)].
21
Reference ID: 3196017
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12.3 Pharmacokinetics
Absorption
PRILOSEC Delayed-Release Capsules contain an enteric-coated
granule formulation of omeprazole (because omeprazole is acid-
labile), so that absorption of omeprazole begins only after the
granules leave the stomach. Absorption is rapid, with peak plasma
levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma
concentrations of omeprazole and AUC are approximately
proportional to doses up to 40 mg, but because of a saturable first-
pass effect, a greater than linear response in peak plasma
concentration and AUC occurs with doses greater than 40 mg.
Absolute bioavailability (compared with intravenous administration)
is about 30-40% at doses of 20-40 mg, due in large part to
presystemic metabolism. In healthy subjects the plasma half-life is 0.5
to 1 hour, and the total body clearance is 500-600 mL/min.
Based on a relative bioavailability study, the AUC and Cmax of
PRILOSEC (omeprazole magnesium) for Delayed-Release Oral
Suspension were 87% and 88% of those for PRILOSEC Delayed-
Release Capsules, respectively.
The bioavailability of omeprazole increases slightly upon repeated
administration of PRILOSEC Delayed-Release Capsules.
PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when
administered with and without applesauce. However, PRILOSEC
Delayed-Release Capsule 20 mg was not bioequivalent when
administered with and without applesauce. When administered with
applesauce, a mean 25% reduction in Cmax was observed without a
significant change in AUC for PRILOSEC Delayed-Release Capsule
20 mg. The clinical relevance of this finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450
(CYP) enzyme system.
Excretion
Following single dose oral administration of a buffered solution of
omeprazole, little if any unchanged drug was excreted in urine. The
majority of the dose (about 77%) was eliminated in urine as at least
six metabolites. Two were identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was
recoverable in feces. This implies a significant biliary excretion of the
metabolites of omeprazole. Three metabolites have been identified in
plasma — the sulfide and sulfone derivatives of omeprazole, and
hydroxyomeprazole. These metabolites have very little or no
antisecretory activity.
22
Reference ID: 3196017
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Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with
clarithromycin 500 mg every 8 hours to healthy adult male subjects.
The steady state plasma concentrations of omeprazole were increased
(Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34%
respectively) by the concomitant administration of clarithromycin.
The observed increases in omeprazole plasma concentration were
associated with the following pharmacological effects. The mean 24
hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin
were increased by the concomitant administration of omeprazole. For
clarithromycin, the mean Cmax was 10% greater, the mean Cmin was
27% greater, and the mean AUC0-8 was 15% greater when
clarithromycin was administered with omeprazole than when
clarithromycin was administered alone. Similar results were seen for
14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean
Cmin was 57% greater, and the mean AUC0-8 was 45% greater.
Clarithromycin concentrations in the gastric tissue and mucus were
also increased by concomitant administration of omeprazole.
Table 2
Clarithromycin Tissue Concentrations
2 hours after Dose
1
Clarithromycin +
Tissue
Clarithromycin
Omeprazole
Antrum
10.48 ± 2.01 (n = 5)
19.96 ± 4.71 (n = 5)
Fundus
20.81 ± 7.64 (n = 5)
24.25 ± 6.37 (n = 5)
Mucus
4.15 ± 7.74 (n = 4)
39.29 ± 32.79 (n = 4)
1Mean ± SD (µg/g)
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the
elderly, and bioavailability was increased. Omeprazole was 76%
bioavailable when a single 40 mg oral dose of omeprazole (buffered
solution) was administered to healthy elderly volunteers, versus 58%
in young volunteers given the same dose. Nearly 70% of the dose was
recovered in urine as metabolites of omeprazole and no unchanged
drug was detected. The plasma clearance of omeprazole was 250
mL/min (about half that of young volunteers) and its plasma half-life
averaged one hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in
pediatric patients 2 to 16 years of age:
Table 3
23
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Pharmacokinetic Parameters of Omeprazole Following Single
and Repeated Oral Administration in Pediatric Populations
Compared with Adults
Single or
Children†
Children†
Adults‡
Repeated
< 20 kg
> 20 kg
(mean
Oral Dosing
2-5 years
6-16
76 kg)
/Parameter
10 mg
years
23-29
20 mg
years
(n=12)
Single Dosing
Cmax *
288
495
668
(ng/mL)
(n=10)
(n=49)
AUC*
511
1140
1220
(ng h/mL)
(n=7)
(n=32)
Repeated Dosing
Cmax *
539
851
1458
(ng/mL)
(n=4)
(n=32)
AUC*
1179
2276
3352
(ng h/mL)
(n=2)
(n=23)
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
†Data from single and repeated dose studies
‡Data from a single and repeated dose study
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children
(2 to 5 years of age) have lower AUCs than children 6 to 16 years of
age or adults; AUCs of the latter two groups did not differ. [See
Dosage and Administration (2)]
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased
to approximately 100% compared with an I.V. dose, reflecting
decreased first-pass effect, and the plasma half-life of the drug
increased to nearly 3 hours compared with the half-life in normals of
0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a
value of 500-600 mL/min in normal subjects. Dose reduction,
particularly where maintenance of healing of erosive esophagitis is
indicated, for the hepatically impaired should be considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance
ranged between 10 and 62 mL/min/1.73 m2, the disposition of
omeprazole was very similar to that in healthy volunteers, although
there was a slight increase in bioavailability. Because urinary
excretion is a primary route of excretion of omeprazole metabolites,
their elimination slowed in proportion to the decreased creatinine
clearance. No dose reduction is necessary in patients with renal
impairment.
Asian Population
24
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In pharmacokinetic studies of single 20 mg omeprazole doses, an
increase in AUC of approximately four-fold was noted in Asian
subjects compared with Caucasians. Dose reduction, particularly
where maintenance of healing of erosive esophagitis is indicated, for
Asian subjects should be considered.
12.4 Microbiology
Omeprazole and clarithromycin dual therapy and omeprazole,
clarithromycin and amoxicillin triple therapy have been shown to be
active against most strains of Helicobacter pylori in vitro and in
clinical infections as described in the Indications and Usage section
(1.1).
Helicobacter
Helicobacter pylori- Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the
omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3%
(41/439) in omeprazole/clarithromycin/amoxicillin triple therapy
studies (1, 2, and 3).
Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were
found in 99.3% (436/439) of the patients in the
omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2,
and 3). Amoxicillin pretreatment minimum inhibitory concentrations
(MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of
whom were in the clarithromycin and amoxicillin study arm. One
patient had an unconfirmed pretreatment amoxicillin minimum
inhibitory concentration (MIC) of > 256 µg/mL by Etest®.
Table 4
Clarithromycin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a
Clarithromycin Pretreatment Results
Clarithromycin Post-treatment Results
H. pylori negative –
eradicated
H. pylori positive – not eradicated
Post-treatment susceptibility results
S b
I b
R b
No MIC
Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed
by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5)
Susceptible b
108
72
1
26
9
Intermediate b
1
1
Resistant b
4
4
Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice
daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies
1, 2)
Susceptible b
171
153
7
3
8
Intermediateb
Resistant b
14
4
1
6
3
aIncludes only patients with pretreatment clarithromycin susceptibility test results
bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC 0.5 – 1.0 µg/mL, Resistant (R) MIC ≥ 2
µg/mL
25
Reference ID: 3196017
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Patients not eradicated of H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy or
omeprazole/clarithromycin dual therapy will likely have
clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with
clarithromycin resistant H. pylori should not be treated with any of
the following: omeprazole/clarithromycin dual therapy,
omeprazole/clarithromycin/amoxicillin triple therapy, or other
regimens which include clarithromycin as the sole antimicrobial
agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
In the triple therapy clinical trials, 84.9% (157/185) of the patients in
the omeprazole/clarithromycin/amoxicillin treatment group who had
pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were
eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment
susceptibility test results and 17 had post-treatment H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed
triple therapy also had post-treatment H. pylori isolates with
clarithromycin resistant MICs.
Susceptibility Test for Helicobacter pylori
For susceptibility testing information about Helicobacter pylori, see
Microbiology section in prescribing information for clarithromycin
and amoxicillin.
Effects on Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including proton pump
inhibitors, increases gastric counts of bacteria normally present in the
gastrointestinal tract. Treatment with proton pump inhibitors may
lead to slightly increased risk of gastrointestinal infections such as
Salmonella and Campylobacter and, in hospitalized patients, possibly
also Clostridium difficile.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily
doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57
times a human dose of 20 mg/day, as expressed on a body surface
area basis) produced gastric ECL cell carcinoids in a dose-related
manner in both male and female rats; the incidence of this effect was
markedly higher in female rats, which had higher blood levels of
omeprazole. Gastric carcinoids seldom occur in the untreated rat. In
addition, ECL cell hyperplasia was present in all treated groups of
both sexes. In one of these studies, female rats were treated with 13.8
mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day,
based on body surface area) for one year, and then followed for an
additional year without the drug. No carcinoids were seen in these
26
Reference ID: 3196017
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rats. An increased incidence of treatment-related ECL cell hyperplasia
was observed at the end of one year (94% treated vs 10% controls).
By the second year the difference between treated and control rats
was much smaller (46% vs 26%) but still showed more hyperplasia in
the treated group. Gastric adenocarcinoma was seen in one rat (2%).
No similar tumor was seen in male or female rats treated for two
years. For this strain of rat no similar tumor has been noted
historically, but a finding involving only one tumor is difficult to
interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain
astrocytomas were found in a small number of males that received
omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to
6.5 times the human dose on a body surface area basis). No
astrocytomas were observed in female rats in this study. In a 2-year
carcinogenicity study in Sprague-Dawley rats, no astrocytomas were
found in males or females at the high dose of 140.8 mg/kg/day (about
57 times the human dose on a body surface area basis). A 78-week
mouse carcinogenicity study of omeprazole did not show increased
tumor occurrence, but the study was not conclusive. A 26-week p53
(+/-) transgenic mouse carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an in vitro human
lymphocyte chromosomal aberration assay, in one of two in vivo
mouse micronucleus tests, and in an in vivo bone marrow cell
chromosomal aberration assay. Omeprazole was negative in the in
vitro Ames test, an in vitro mouse lymphoma cell forward mutation
assay, and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times
the human dose on a body surface area basis) was found to have no
effect on fertility and reproductive performance.
In 24-month carcinogenicity studies in rats, a dose-related significant
increase in gastric carcinoid tumors and ECL cell hyperplasia was
observed in both male and female animals [See Warnings and
Precautions (5)] Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other proton
pump inhibitors or high doses of H2-receptor antagonists.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproductive studies conducted with omeprazole in rats at oral doses
up to 138 mg/kg/day (about 56 times the human dose on a body
surface area basis) and in rabbits at doses up to 69 mg/kg/day (about
56 times the human dose on a body surface area basis) did not
disclose any evidence for a teratogenic potential of omeprazole. In
rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about
5.5 to 56 times the human dose on a body surface area basis)
produced dose-related increases in embryo-lethality, fetal resorptions,
and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity
and postnatal developmental toxicity were observed in offspring
27
Reference ID: 3196017
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resulting from parents treated with omeprazole at 13.8 to 138.0
mg/kg/day (about 5.6 to 56 times the human doses on a body surface
area basis).
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
Active Duodenal Ulcer— In a multicenter, double-blind, placebo-
controlled study of 147 patients with endoscopically documented
duodenal ulcer, the percentage of patients healed (per protocol) at 2
and 4 weeks was significantly higher with PRILOSEC 20 mg once
daily than with placebo (p ≤ 0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Placebo
20 mg a.m.
a.m.
Week 2
(n = 99)
* 41
(n = 48)
13
Week 4
* 75
27
*(p < 0.01)
Complete daytime and nighttime pain relief occurred significantly
faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in
patients treated with placebo. At the end of the study, significantly
more patients who had received PRILOSEC had complete relief of
daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).
In a multicenter, double-blind study of 293 patients with
endoscopically documented duodenal ulcer, the percentage of patients
healed (per protocol) at 4 weeks was significantly higher with
PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p <
0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg a.m.
150 mg twice daily
(n = 145)
(n = 148)
Week 2
42
34
Week 4
*82
63
*(p < 0.01)
Healing occurred significantly faster in patients treated with
PRILOSEC than in those treated with ranitidine 150 mg b.i.d. (p <
0.01).
In a foreign multinational randomized, double-blind study of 105
patients with endoscopically documented duodenal ulcer, 20 mg and
40 mg of PRILOSEC were compared with 150 mg b.i.d. of ranitidine
at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were
statistically superior (per protocol) to ranitidine, but 40 mg was not
28
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superior to 20 mg of PRILOSEC, and at 8 weeks there was no
significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
20 mg
(n = 34)
40 mg
(n = 36)
Ranitidine
150 mg twice
daily
(n = 35)
Week 2
*83
*83
53
Week 4
82
*97
*100
Week 8
94
100
100
*(p < 0.01)
H. pylori Eradication in Patients with Duodenal Ulcer
Disease
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)— Three
U.S., randomized, double-blind clinical studies in patients with H.
pylori infection and duodenal ulcer disease (n = 558) compared
PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin
plus amoxicillin. Two studies (1 and 2) were conducted in patients
with an active duodenal ulcer, and the other study (3) was conducted
in patients with a history of a duodenal ulcer in the past 5 years but
without an ulcer present at the time of enrollment. The dose regimen
in the studies was PRILOSEC 20 mg twice daily plus clarithromycin
500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or
clarithromycin 500 mg. twice daily plus amoxicillin 1 g twice daily
for 10 days. In studies 1 and 2, patients who took the omeprazole
regimen also received an additional 18 days of PRILOSEC 20 mg
once daily. Endpoints studied were eradication of H. pylori and
duodenal ulcer healing (studies 1 and 2 only). H. pylori status was
determined by CLOtest®, histology and culture in all three studies.
For a given patient, H. pylori was considered eradicated if at least two
of these tests were negative, and none was positive.
The combination of omeprazole plus clarithromycin plus amoxicillin
was effective in eradicating H. pylori.
Table 5
Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
% of Patients Cured [95% Confidence Interval]
PRILOSEC +clarithromycin
Clarithromycin +amoxicillin
+amoxicillin
Per-Protocol †
Intent-to-Treat ‡
Per-Protocol †
Intent-to-Treat ‡
Study 1
*77 [64, 86]
(n = 64)
*69 [57, 79]
(n = 80)
43 [31, 56]
(n = 67)
37 [27, 48]
(n = 84)
Study 2
*78 [67, 88]
(n = 65)
*73 [61, 82]
(n = 77)
41 [29, 54]
(n = 68)
36 [26, 47]
(n = 83)
Study 3
*90 [80, 96]
(n = 69)
*83 [74, 91]
(n = 84)
33 [24, 44]
(n = 93)
32 [23, 42]
(n = 99)
† Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer
within 5 years, study 3) and H. pylori infection at baseline defined as
at least two of three positive endoscopic tests from CLOtest ,
29
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histology, and/or culture. Patients were included in the analysis if
they completed the study. Additionally, if patients dropped out of
the study due to an adverse event related to the study drug, they were
included in the analysis as failures of therapy. The impact of
eradication on ulcer recurrence has not been assessed in patients with
a past history of ulcer.
‡ Patients were included in the analysis if they had documented
H. pylori infection at baseline and had confirmed duodenal ulcer
disease. All dropouts were included as failures of therapy.
* (p < 0.05) versus clarithromycin plus amoxicillin.
Dual Therapy (PRILOSEC/clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7)
evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg
three times daily for 14 days, followed by PRILOSEC 20 mg once
daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study
6) for an additional 14 days in patients with active duodenal ulcer
associated with H. pylori. Studies 4 and 5 were conducted in the U.S.
and Canada and enrolled 242 and 256 patients, respectively. H. pylori
infection and duodenal ulcer were confirmed in 219 patients in Study
4 and 228 patients in Study 5. These studies compared the
combination regimen to PRILOSEC and clarithromycin
monotherapies. Studies 6 and 7 were conducted in Europe and
enrolled 154 and 215 patients, respectively. H. pylori infection and
duodenal ulcer were confirmed in 148 patients in study 6 and 208
patients in Study 7. These studies compared the combination regimen
with omeprazole monotherapy. The results for the efficacy analyses
for these studies are described below. H. pylori eradication was
defined as no positive test (culture or histology) at 4 weeks following
the end of treatment, and two negative tests were required to be
considered eradicated of H. pylori. In the per-protocol analysis, the
following patients were excluded: dropouts, patients with missing H.
pylori tests post-treatment, and patients that were not assessed for H.
pylori eradication because they were found to have an ulcer at the end
of treatment.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori.
Table 6
30
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H. pylori Eradication Rates (Per-Protocol Analysis
at 4 to 6 Weeks)
% of Patients Cured [95% Confidence Interval]
PRILOSEC +
Clarithromycin
PRILOSEC
Clarithromycin
U.S. Studies
Study 4
74 [60, 85] †‡
(n = 53)
0 [0, 7]
(n = 54)
31 [18, 47]
(n = 42)
Study 5
64 [51, 76] †‡
(n = 61)
0 [0, 6]
(n = 59)
39 [24, 55]
(n = 44)
Non U.S. Studies
Study 6
83 [71, 92] ‡
(n = 60)
1 [0, 7]
(n = 74)
N/A
Study 7
74 [64, 83] ‡
(n = 86)
1 [0, 6]
(n = 90)
N/A
†Statistically significantly higher than clarithromycin
monotherapy (p < 0.05)
‡Statistically significantly higher than omeprazole
monotherapy (p < 0.05)
Ulcer healing was not significantly different when clarithromycin was
added to omeprazole therapy compared with omeprazole therapy
alone.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori and reduced duodenal ulcer recurrence.
Table 7
Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status
% of Patients with Ulcer Recurrence
H. pylori eradicated#
H. pylori not eradicated#
U.S. Studies †
6 months post-treatment
Study 4
*35
60
(n = 49)
(n = 88)
Study 5
*8
60
(n = 53)
(n = 106)
Non U.S. Studies ‡
6 months post-treatment
Study 6
*5
46
(n = 43)
(n = 78)
Study 7
*6
43
(n = 53)
(n = 107)
12 months post-treatment
Study 6
*5
68
(n = 39)
(n = 71)
#H. pylori eradication status assessed at same time point as ulcer recurrence
†Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment
arms
‡Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
*(p < 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori
eradicated
14.2 Gastric Ulcer
In a U.S. multicenter, double-blind, study of omeprazole 40 mg once
daily, 20 mg once daily, and placebo in 520 patients with
endoscopically diagnosed gastric ulcer, the following results were
obtained.
31
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Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
Week 4
Week 8
PRILOSEC
20 mg once daily
(n = 202)
47.5**
74.8**
PRILOSEC
40 mg once daily
(n = 214)
55.6**
82.7**,+
Placebo
(n = 104)
30.8
48.1
**(p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
+(p < 0.05) PRILOSEC 40 mg versus 20 mg
For the stratified groups of patients with ulcer size less than or equal
to 1 cm, no difference in healing rates between 40 mg and 20 mg was
detected at either 4 or 8 weeks. For patients with ulcer size greater
than 1 cm, 40 mg was significantly more effective than 20 mg at 8
weeks.
In a foreign, multinational, double-blind study of 602 patients with
endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily,
20 mg once daily, and ranitidine 150 mg twice a day were evaluated.
Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
40 mg once daily
150 mg twice daily
(n = 200)
(n = 187)
(n = 199)
Week 4
63.5
56.3
78.1**,++
Week 8
81.5
78.4
91.4**,++
** (p < 0.01) PRILOSEC 40 mg versus ranitidine
++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
14.3 Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo-controlled study was conducted in Scandinavia to compare
the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4
weeks in the treatment of heartburn and other symptoms in GERD
patients without erosive esophagitis. Results are shown below.
% Successful Symptomatic Outcomea
PRILOSEC
PRILOSEC
Placebo
20 mg a.m.
10 mg a.m.
a.m.
All patients
46*,†
31†
13
(n = 105)
(n = 205)
(n = 199)
Patients with
14
56*,†
36†
confirmed GERD
(n = 59)
(n = 115)
(n = 109)
aDefined as complete resolution of heartburn
*(p < 0.005) versus 10 mg
†(p < 0.005) versus placebo
14.4 Erosive Esophagitis
In a U.S. multicenter double-blind placebo controlled study of 20 mg
or 40 mg of PRILOSEC Delayed-Release Capsules in patients with
symptoms of GERD and endoscopically diagnosed erosive
32
Reference ID: 3196017
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esophagitis of grade 2 or above, the percentage healing rates (per
protocol) were as follows:
20 mg PRILOSEC
40 mg PRILOSEC
Placebo
Week
(n = 83)
(n = 87)
(n = 43)
4
39**
45**
7
8
74**
75**
14
** (p < 0.01) PRILOSEC versus placebo.
In this study, the 40 mg dose was not superior to the 20 mg dose of
PRILOSEC in the percentage healing rate. Other controlled clinical
trials have also shown that PRILOSEC is effective in severe GERD.
In comparisons with histamine H2-receptor antagonists in patients
with erosive esophagitis, grade 2 or above, PRILOSEC in a dose of
20 mg was significantly more effective than the active controls.
Complete daytime and nighttime heartburn relief occurred
significantly faster (p < 0.01) in patients treated with PRILOSEC than
in those taking placebo or histamine H2- receptor antagonists.
In this and five other controlled GERD studies, significantly more
patients taking 20 mg omeprazole (84%) reported complete relief of
GERD symptoms than patients receiving placebo (12%).
Long Term Maintenance Of Healing of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled
study, two dose regimens of PRILOSEC were studied in patients with
endoscopically confirmed healed esophagitis. Results to determine
maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
PRILOSEC
PRILOSEC
20 mg 3 days
20 mg once daily
per week
Placebo
(n = 138)
(n = 137)
(n = 131)
Percent in
endoscopic
remission at
6 months
34
11
*70
∗(p < 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 20 mg 3 consecutive days per week or
placebo.
In an international multicenter double-blind study, PRILOSEC 20 mg
daily and 10 mg daily were compared with ranitidine 150 mg twice
daily in patients with endoscopically confirmed healed esophagitis.
The table below provides the results of this study for maintenance of
healing of erosive esophagitis.
33
Reference ID: 3196017
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Life Table Analysis
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
10 mg once daily
150 mg twice daily
(n = 131)
(n = 133)
(n = 128)
Percent in
endoscopic
remission at
12 months
46
*77
‡58
*
(p = 0.01) PRILOSEC 20 mg once daily. versus PRILOSEC 10 mg once daily or
Ranitidine.
‡ (p = 0.03) PRILOSEC 10 mg once daily. versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for
maintenance after healing 20 mg daily of PRILOSEC was effective,
while 10 mg did not demonstrate effectiveness.
14.5 Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory
conditions, such as Zollinger-Ellison (ZE) syndrome with or without
multiple endocrine adenomas, PRILOSEC Delayed-Release Capsules
significantly inhibited gastric acid secretion and controlled associated
symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg
every other day to 360 mg per day maintained basal acid secretion
below 10 mEq/hr in patients without prior gastric surgery, and below
5 mEq/hr in patients with prior gastric surgery.
Initial doses were titrated to the individual patient need, and
adjustments were necessary with time in some patients [See Dosage
and Administration (2)] PRILOSEC was well tolerated at these high
dose levels for prolonged periods (> 5 years in some patients). In
most ZE patients, serum gastrin levels were not modified by
PRILOSEC. However, in some patients serum gastrin increased to
levels greater than those present prior to initiation of omeprazole
therapy. At least 11 patients with ZE syndrome on long-term
treatment with PRILOSEC developed gastric carcinoids. These
findings are believed to be a manifestation of the underlying
condition, which is known to be associated with such tumors, rather
than the result of the administration of PRILOSEC. [See Adverse
Reactions (6)]
14.6 Pediatric GERD
Symptomatic GERD
The effectiveness of PRILOSEC for the treatment of nonerosive
GERD in pediatric patients 1 to 16 years of age is based in part on
data obtained from 125 pediatric patients in two uncontrolled Phase
III studies. [See Use in Specific Populations (8.4)]
The first study enrolled 12 pediatric patients 1 to 2 years of age with a
history of clinically diagnosed GERD. Patients were administered a
single dose of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8
weeks as an open capsule in 8.4% sodium bicarbonate solution.
Seventy-five percent (9/12) of the patients had vomiting/regurgitation
episodes decreased from baseline by at least 50%.
34
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The second study enrolled 113 pediatric patients 2 to 16 years of age
with a history of symptoms suggestive of nonerosive GERD. Patients
were administered a single dose of omeprazole (10 mg or 20 mg,
based on body weight) for 4 weeks either as an intact capsule or as an
open capsule in applesauce. Successful response was defined as no
moderate or severe episodes of either pain-related symptoms or
vomiting/regurgitation during the last 4 days of treatment. Results
showed success rates of 60% (9/15; 10 mg omeprazole) and 59%
(58/98; 20 mg omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive
esophagitis in pediatric patients 1 to 16 years of age required doses
that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were
initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7
mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than
6% of a 24-hour study). After titration, patients remained on
treatment for 3 months. Forty-four percent of the patients were healed
on a dose of 0.7 mg/kg body weight; most of the remaining patients
were healed with 1.4 mg/kg after an additional 3 months’ treatment.
Erosive esophagitis was healed in 51 of 57 (90%) children who
completed the first course of treatment in the healing phase of the
study. In addition, after 3 months of treatment, 33% of the children
had no overall symptoms, 57% had mild reflux symptoms, and 40%
had less frequent regurgitation/vomiting.
Maintenance of Healing of Erosive Esophagitis
In an uncontrolled, open-label study of maintenance of healing of
erosive esophagitis in 46 pediatric patients, 54% of patients required
half the healing dose. The remaining patients increased the healing
dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire
maintenance period, or returned to half the dose before completion.
Of the 46 patients who entered the maintenance phase, 19 (41%) had
no relapse. In addition, maintenance therapy in erosive esophagitis
patients resulted in 63% of patients having no overall symptoms.
15
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods
for Dilution Antimicrobial Susceptibility Tests for Bacteria That
Grow Aerobically—Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January
2000.
16
HOW SUPPLIED/STORAGE AND HANDLING
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body. They are supplied as follows:
35
Reference ID: 3196017
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NDC 0186-0606-31 unit of use bottles of 30
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body. They are supplied as follows:
NDC 0186-0742-31 unit of use bottles of 30
NDC 0186-0742-82 bottles of 1000.
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body. They are supplied as follows:
NDC 0186-0743-31 unit of use bottles of 30
NDC 0186-0743-68 bottles of 100
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules. PRILOSEC unit dose packets are supplied as
follows:
NDC 0186-0625-01 unit dose packages of 30: 2.5 mg packets
NDC 0186-0610-01 unit dose packages of 30: 10 mg packets
Storage
Store PRILOSEC Delayed-Release Capsules in a tight container
protected from light and moisture. Store between 15°C and 30°C
(59°F and 86°F).
Store PRILOSEC For Delayed-Release Oral Suspension at 25°C
(77°F); excursions permitted to 15 – 30°C (59 – 86°F). [See USP
Controlled Room Temperature].
17
PATIENT COUNSELING INFORMATION
PRILOSEC should be taken before eating. Patients should be
informed that the PRILOSEC Delayed-Release Capsule should be
swallowed whole.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
36
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
Advise patients to immediately report and seek care for diarrhea that
does not improve. This may be a sign of Clostridium difficile
associated diarrhea [see Warnings and Precautions (5.3)].
Advise patients to immediately report and seek care for any
cardiovascular or neurological symptoms including palpitations,
dizziness, seizures, and tetany as these may be signs of
hypomagnesemia [see Warnings and Precautions (5.6)].
PRILOSEC is a trademark of the AstraZeneca group of companies.
©AstraZeneca 2012
Manufactured for: AstraZeneca LP, Wilmington, DE 19850
37
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
PRILOSEC (pry-lo-sec)
(omeprazole)
Delayed-Release Capsules
PRILOSEC (pry-lo-sec)
(omeprazole magnesium)
for Delayed-Release Oral Suspension
Read this Medication Guide before you start taking
PRILOSEC and each time you get a refill. There may be new
information. This information does not take the place of
talking with your doctor provider about your medical
condition or your treatment.
What is the most important information I should
know about PRILOSEC?
PRILOSEC may help your acid-related symptoms, but
you could still have serious stomach problems. Talk
with your doctor.
PRILOSEC can cause serious side effects, including:
• Diarrhea. PRILOSEC may increase your risk of
getting severe diarrhea. This diarrhea may be caused
by an infection (Clostridium difficile) in your
intestines.
Call your doctor right away if you have watery stool,
stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily
doses of proton pump inhibitor medicines for a long
period of time (a year or longer) may have an
increased risk of fractures of the hip, wrist, or spine.
You should take PRILOSEC exactly as prescribed, at
the lowest dose possible for your treatment and for
the shortest time needed. Talk to your doctor about
your risk of bone fracture if you take PRILOSEC.
PRILOSEC can have other serious side effects. See “What
are the possible side effects of PRILOSEC?”
What is PRILOSEC?
PRILOSEC is a prescription medicine called a proton pump
inhibitor (PPI). PRILOSEC reduces the amount of acid in
your stomach.
PRILOSEC is used in adults:
• for up to 8 weeks for the healing of duodenal ulcers.
The duodenal area is the area where food passes
when it leaves the stomach.
1
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
with certain antibiotics to treat an infection caused by
bacteria called H. pylori. Sometimes H. pylori
bacteria can cause duodenal ulcers. The infection
needs to be treated to prevent the ulcers from coming
back.
• for up to 8 weeks for healing stomach ulcers
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
GERD happens when acid in your stomach backs up
into the tube (esophagus) that connects your mouth
to your stomach. This may cause a burning feeling in
your chest or throat, sour taste, or burping.
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE). If needed, your doctor may decide to prescribe
another 4 weeks of PRILOSEC.
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used for
longer than 12 months (1 year) for this purpose.
• for the long-term treatment of conditions where your
stomach makes too much acid. This includes a rare
condition called Zollinger-Ellison Syndrome.
For children 1 to 16 years of age, PRILOSEC is used:
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE)
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used longer
than 12 months (1 year) for this purpose.
It is not known if PRILOSEC is safe and effective for the
treatment of gastroesophageal reflux disease (GERD)
in children under 1 year of age.
Who should not take PRILOSEC?
Do not take PRILOSEC if you:
• are allergic to omeprazole or any of the ingredients in
PRILOSEC. See the end of this Medication Guide for a
complete list of ingredients in PRILOSEC.
• are allergic to any other Proton Pump Inhibitor (PPI)
medicine.
What should I tell my doctor before taking PRILOSEC?
2
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Before you take PRILOSEC, tell your doctor if you:
• have been told that you have low magnesium levels
in your blood
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not
known if PRILOSEC will harm your unborn baby.
• are breastfeeding or plan to breastfeed. PRILOSEC
can pass into your breast milk and may harm your
baby. You and your doctor should decide if you will
take PRILOSEC or breastfeed. You should not do both.
Talk to your doctor about the best way to feed your
baby if you breastfeed.
Tell your doctor about all of the medicines you take
including prescription and non-prescription drugs, anti
cancer drugs, vitamins and herbal supplements. PRILOSEC
may affect how other medicines work, and other medicines
may affect how PRILOSEC works.
Especially tell your doctor if you take:
• atazanavir (Reyataz)
• nelfinavir (Viracept)
• saquinavir (Fortovase)
• cilostazol (Pletal)
• ketoconazole (Nizoral)
• voriconazole (Vfend)
• an antibiotic that contains ampicillin, amoxicillin or
clarithromycin
• products that contain iron
• warfarin (Coumadin, Jantoven)
• digoxin (Lanoxin)
• tacrolimus (Prograf)
• diazepam (Valium)
• phenytoin (Dilantin)
• disulfiram (Antabuse)
• clopidogrel (Plavix)
• St. John’s Wort (Hypericum perforatum)
• rifampin (Rimactane, Rifater, Rifamate),
• erlotinib (Tarceva)
• methotrexate
Ask your doctor or pharmacist for a list of these
medicines if you are not sure.
Know the medicines that you take. Keep a list of them to
show your doctor and pharmacist when you get a new
medicine.
How should I take PRILOSEC?
• Take PRILOSEC exactly as prescribed by your doctor.
3
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not change your dose or stop PRILOSEC without
talking to your doctor.
• Take PRILOSEC at least 1 hour before a meal.
• Swallow PRILOSEC capsules whole. Do not chew or
crush PRILOSEC Capsules.
• If you have trouble swallowing PRILOSEC Capsules,
you may take as follows:
o Place 1 tablespoon of applesauce into a clean
bowl.
o Carefully open the capsule and empty the
contents (pellets) onto the applesauce. Mix the
pellets with the applesauce.
o Swallow the applesauce and pellet mixture
right away with a glass of cool water. Do not
chew or crush the pellets. Do not store the
applesauce and pellet mixture for later use.
• If you forget to take a dose of PRILOSEC, take it as
soon as you remember. If it is almost time for your
next dose, do not take the missed dose. Take the
next dose on time. Do not take a double dose to
make up for a missed dose.
• If you take too much PRILOSEC, tell your doctor right
away.
• See the “Instructions for Use” at the end of this
Medication Guide for instructions on how to take
PRILOSEC For Delayed-Release Oral Suspension, and
how to mix and give PRILOSEC For Delayed-Release
Oral Suspension, through a nasogastric tube or
gastric tube.
What are the possible side effects of PRILOSEC?
PRILOSEC can cause serious side effects, including:
• See “What is the most important information I
should know about PRILOSEC?”
• Chronic (lasting a long time) inflammation of
the stomach lining (Atrophic Gastritis). Using
PRILOSEC for a long period of time may increase the
risk of inflammation to your stomach lining. You may
or may not have symptoms. Tell your doctor if you
have stomach pain, nausea, vomiting, or weight loss.
• Low magnesium levels in your body. This
problem can be serious. Low magnesium can happen
in some people who take a proton pump inhibitor
medicine for at least 3 months. If low magnesium
levels happen, it is usually after a year of treatment.
You may or may not have symptoms of low
magnesium.
Tell your doctor right away if you develop any of
these symptoms:
4
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
seizures
•
dizziness
•
abnormal or fast heart beat
•
jitteriness
•
jerking movements or shaking (tremors)
•
muscle weakness
•
spasms of the hands and feet
•
cramps or muscle aches
•
spasm of the voice box
Your doctor may check the level of magnesium in
your body before you start taking PRILOSEC or during
treatment if you will be taking PRILOSEC for a long
period of time.
The most common side effects with PRILOSEC in adults and
children include:
•
headache
•
stomach pain
•
nausea
•
diarrhea
•
vomiting
•
gas
In addition to the side effects listed above, the most
common side effects in children 1 to 16 years of age
include:
•
respiratory system events
•
fever
Other side effects:
Serious allergic reactions. Tell your doctor if you get any
of the following symptoms with PRILOSEC:
•
rash
•
face swelling
•
throat tightness
•
difficulty breathing
Your doctor may stop PRILOSEC if these symptoms
happen.
Tell your doctor if you have any side effect that bothers you
or that do not go away. These are not all the possible side
effects with PRILOSEC.
Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
5
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store PRILOSEC?
• Store PRILOSEC Delayed-Release Capsules at room
temperature between 59°F to 86°F (15°C to 30°C).
• Store PRILOSEC Delayed-Release Oral Suspension at
room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the container of PRILOSEC Delayed-Release
Capsules closed tightly.
• Keep the container of PRILOSEC Delayed-Release
Capsules dry and away from light.
Keep PRILOSEC and all medicines out of the reach of
children.
General information about PRILOSEC
Medicines are sometimes prescribed for purposes other than
those listed in a Medication Guide. Do not use PRILOSEC for
a condition for which it was not prescribed. Do not give
PRILOSEC to other people, even if they have the same
symptoms you have. It may harm them.
This Medication Guide summarizes the most important
information about PRILOSEC. For more information, ask
your doctor. You can ask your doctor or pharmacist for
information that is written for healthcare professionals.
For more information, go to www.astrazeneca-us.com or call
1-800-236-9933.
Instructions for Use
For instructions on taking Delayed-Release Capsules, please
see “How should I take PRILOSEC?”
Take PRILOSEC For Delayed-Release Oral Suspension as
follows:
• PRILOSEC For Delayed-Release Oral Suspension
comes in packets containing 2.5 mg and 10 mg
strengths.
• You should use an oral syringe to measure the
amount of water needed to mix your dose. Ask your
pharmacist for an oral syringe.
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If you or your child are instructed to use more than
one packet for your prescribed dose, follow the
6
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mixing instructions provided by your pharmacist or
doctor.
• Stir.
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes. If not used within
30 minutes, throw away this dose and mix a new
dose.
• If any medicine remains after drinking, add more
water, stir, and drink right away.
PRILOSEC For Delayed-Release Oral Suspension may be
given through a nasogastric tube (NG tube) or gastric tube,
as prescribed by your doctor. Follow the instructions below:
PRILOSEC For Delayed-Release Oral Suspension:
• PRILOSEC Delayed-Release Oral Suspension comes in
packets containing 2.5 mg and 10 mg strengths.
• Use only a catheter tipped syringe to give PRILOSEC
through a NG tube or gastric tube (French size 6 or
larger).
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• Shake the syringe right away and then leave it for 2
to 3 minutes to thicken.
• Shake the syringe and give the medicine through the
NG or gastric tube within 30 minutes.
• Refill the syringe with the same amount of water
(either 5 mL or 15 mL of water depending on your
dose).
• Shake the syringe and flush any remaining medicine
from the NG tube or gastric tube into the stomach.
What are the ingredients in PRILOSEC?
Active ingredient in PRILOSEC Delayed-Release
Capsules: omeprazole
Inactive ingredients in PRILOSEC Delayed-Release
Capsules: cellulose, disodium hydrogen phosphate,
hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate. Capsule shells: gelatin-NF, FD&C Blue
#1, FD&C Red #40, D&C Red #28, titanium dioxide,
synthetic black iron oxide, isopropanol, butyl alcohol, FD&C
Blue #2, D&C Red #7 Calcium Lake, and, in addition, the 10
mg and 40 mg capsule shells also
contain D&C Yellow #10.
Active ingredient in PRILOSEC For Delayed-Release
Oral Suspension: omeprazole magnesium
7
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive ingredients in PRILOSEC For Delayed-Release
Oral Suspension: glyceryl monostearate, hydroxypropyl
cellulose, hypromellose, magnesium stearate, methacrylic
acid copolymer C, polysorbate, sugar spheres, talc, and
triethyl citrate.
Inactive granules in PRILOSEC For Delayed-Release
Oral Suspension: citric acid, crospovidone, dextrose,
hydroxypropyl cellulose, iron oxide and xantham gum.
This Medication Guide and Instructions for Use has been
approved by the U.S. Food and Drug Adminstration.
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Issued September 2012
PRILOSEC is a registered trademark of the AstraZeneca
group of companies.
©2012 AstraZeneca Pharmaceuticals LP. All rights reserved.
8
Reference ID: 3196017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:59.003548
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019810s096lbl.pdf', 'application_number': 19810, 'submission_type': 'SUPPL ', 'submission_number': 96}
|
11,733
|
_______________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRILOSEC safely and effectively. See full prescribing information for
PRILOSEC.
PRILOSEC (omeprazole) Delayed-Release Capsules and PRILOSEC
(omeprazole magnesium) For Delayed-Release Oral Suspension
INITIAL U.S. APPROVAL: 1989
-------------------------RECENT MAJOR CHANGES-----------------------------
Warnings and Precautions, Interaction with Clopidogrel (5.4)
10/2012
Warnings and Precautions, Clostridium difficile associated
09/2012
diarrhea (5.3)
--------------------------INDICATIONS AND USAGE----------------------------
PRILOSEC is a proton pump inhibitor indicated for:
•
Treatment in adults of duodenal ulcer (1.1) and gastric ulcer (1.2)
•
Treatment in adults and children of gastroesophageal reflux disease
(GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4)
The safety and effectiveness of PRILOSEC in pediatric patients <1 year of
age have not been established. (8.4)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Indication
Omeprazole Dose
Frequency
Treatment of Active
20 mg
Once daily for 4 weeks. Some
Duodenal Ulcer (2.1)
patients may require an
additional 4 weeks
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
Triple Therapy:
PRILOSEC
20 mg
Each drug twice daily for 10
Amoxicillin
1000 mg
days
Clarithromycin
500 mg
Dual Therapy:
PRILOSEC
40 mg
Once daily for 14 days
Clarithromycin
500 mg
Three times daily for 14 days
Gastric Ulcer (2.3)
40 mg
Once daily for 4 to 8 weeks
GERD (2.4)
20 mg
Once daily for 4 to 8 weeks
Maintenance of Healing of
20 mg
Once daily
Erosive Esophagitis (2.5)
Pathological Hypersecretory
60 mg (varies with
Once daily
Conditions (2.6)
individual patient)
Pediatric Patients
(1 to 16 years of age) (2.7)
Weight
Dose
GERD And Maintenance
5 < 10 kg
5 mg
Once daily
of Healing of Erosive
10< 20 kg 10 mg
Esophagitis
> 20 kg
20 mg
----------------------DOSAGE FORMS AND STRENGTHS---------------------
•
PRILOSEC Delayed-Release Capsules, 10 mg, 20 mg and 40 mg (3)
•
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg (3)
---------------------------CONTRAINDICATIONS--------------------------------
Known hypersensitivity to any component of the formulation or substituted
benzimidazoles (angioedema and anaphylaxis have occurred) (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
•
Symptomatic response does not preclude the presence of gastric
malignancy (5.1)
•
Atrophic gastritis: has been noted with long-term therapy (5.2)
•
PPI therapy may be associated with increased risk of Clostridium
difficile associated diarrhea. (5.3)
•
Avoid concomitant use of PRILOSEC with clopidogrel.(5.4)
•
Bone Fracture: Long-term and multiple daily dose PPI therapy may be
associated with an increased risk for osteoporosis-related fractures of the
hip, wrist or spine. (5.5)
•
Hypomagnesemia has been reported rarely with prolonged treatment
with PPIs (5.6)
•
Avoid concomitant use of PRILOSEC with St John’s Wort or rifampin
due to the potential reduction in omeprazole concentrations (5.7, 7.3)
•
Interactions with diagnostic investigations for Neuroendocrine Tumors:
Increases in intragastric pH may result in hypergastrinemia and
enterochromaffin-like cell hyperplasia and increased Choromogranin A
levels which may interfere with diagnostic investigations for
neuroendocrine tumors. (5.8, 12.2)
-------------------------------ADVERSE REACTIONS--------------------------
Adults: Most common adverse reactions in adults (incidence ≥ 2%) are
•
Headache, abdominal pain, nausea, diarrhea, vomiting, and
flatulence (6)
Pediatric patients (1 to 16 years of age):
Safety profile similar to that in adults, except that respiratory system
events and fever were the most frequently reported reactions in pediatric
studies (8.4)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS---------------------------
•
Atazanavir and nelfinavir: PRILOSEC reduces plasma levels of
atazanavir and nelfinavir. Concomitant use is not recommended (7.1)
•
Saquinavir: PRILOSEC increases plasma levels of saquinavir. Monitor
for toxicity and consider dose reduction of saquinavir (7.1)
•
May interfere with drugs for which gastric pH affects bioavailability
(e.g., ketoconazole, iron salts, erlotinib, ampicillin esters, and digoxin).
Patients treated with PRILOSEC and digoxin may need to be monitored
for increases in digoxin toxicity (7.2)
•
Clopidogrel: PRILOSEC decreases exposure to the active metabolite of
clopidogrel. (7.3, 12.3)
•
Cilostazol: PRILOSEC increases systemic exposure of cilostazol and
one of its active metabolites. Consider dose reduction of cilostazol.(7.3)
•
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin,
phenytoin, cyclosporine, disulfiram, benzodiazepines): PRILOSEC can
prolong their elimination. Monitor and determine need for dose
adjustments (7.3)
•
Patients treated with proton pump inhibitors and warfarin may need to
be monitored for increases in INR and prothrombin time (7.3)
•
Combined inhibitor of CYP 2C19 and 3A4 (e.g. voriconazole) may raise
omeprazole levels (7.3)
•
Tacrolimus: PRILOSEC may increase serum levels of tacrolimus (7.4)
•
Methotrexate: PRILOSEC may increase serum levels of methotrexate
(7.7)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
Patients with hepatic impairment:
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis (12.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
Approved Medication Guide.
REVISED: May 2013
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
1.2 Gastric Ulcer (adults)
1.3 Treatment of Gastroesophageal Reflux Disease (GERD)
(adults and pediatric patients)
1.4 Maintenance of Healing of Erosive Esophagitis (adults)
1.5 Pathological Hypersecretory Conditions
2
DOSAGE AND ADMINISTRATION
2.1 Short-Term Treatment of Active Duodenal Ulcer
2.2 H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
2.3 Gastric Ulcer
2.4 Gastroesophageal Reflux Disease (GERD)
2.5 Maintenance of Healing of Erosive Esophagitis
2.6 Pathological Hypersecretory Conditions
2.7 Pediatric Patients
2.8 Alternative Administration Options
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Concomitant Gastric Malignancy
5.2 Atrophic Gastritis
5.3 Clostridium difficile associated diarrhea
5.4 Interaction with Clopidogrel
5.5 Bone Fracture
5.6 Hypomagnesemia
5.7 Comcomitant Use of PRILOSEC with St John’s Wort or
rifampin
5.8 Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
5.9 Concomitant use of PRILOSEC with Methotrexate
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience with PRILOSEC Monotherapy
6.2 Clinical Trials Experience with PRILOSEC in Combination
Therapy for H. pylori Eradication
6.3 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Interference with Antiretroviral Therapy
7.2 Drugs for Which Gastric pH Can Affect Bioavailability
7.3
Effects on Hepatic Metabolism/Cytochrome P-450 Pathways
7.4 Tacrolimus
7.5 Interactions with Investigations of Neuroendocrine Tumors
7.6 Combination Therapy with Clarithromycin
7.7 Methotrexate
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Asian Population
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
14.2 Gastric Ulcer
14.3 Gastroesophageal Reflux Disease (GERD)
14.4 Erosive Esophagitis
14.5 Pathological Hypersecretory Conditions
14.6 Pediatric GERD
15
REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
PRILOSEC is indicated for short-term treatment of active duodenal
ulcer in adults. Most patients heal within four weeks. Some patients
may require an additional four weeks of therapy.
PRILOSEC in combination with clarithromycin and amoxicillin, is
indicated for treatment of patients with H. pylori infection and
duodenal ulcer disease (active or up to 1-year history) to eradicate H.
pylori in adults.
PRILOSEC in combination with clarithromycin is indicated for
treatment of patients with H. pylori infection and duodenal ulcer
disease to eradicate H. pylori in adults.
Eradication of H. pylori has been shown to reduce the risk of
duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage
and Administration (2)].
Among patients who fail therapy, PRILOSEC with clarithromycin is
more likely to be associated with the development of clarithromycin
resistance as compared with triple therapy. In patients who fail
therapy, susceptibility testing should be done. If resistance to
clarithromycin is demonstrated or susceptibility testing is not
possible, alternative antimicrobial therapy should be instituted. [See
Microbiology section (12.4)], and the clarithromycin package insert,
Microbiology section.)
1.2 Gastric Ulcer (adults)
PRILOSEC is indicated for short-term treatment (4-8 weeks) of active
benign gastric ulcer in adults. [See Clinical Studies (14.2)]
1.3
Treatment of Gastroesophageal Reflux Disease
(GERD) (adults and pediatric patients)
Symptomatic GERD
PRILOSEC is indicated for the treatment of heartburn and other
symptoms associated with GERD in pediatric patients and adults.
Erosive Esophagitis
PRILOSEC is indicated for the short-term treatment (4-8 weeks) of
erosive esophagitis that has been diagnosed by endoscopy in pediatric
patients and adults. [See Clinical Studies (14.4)]
3
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of PRILOSEC used for longer than 8 weeks in these
patients has not been established. If a patient does not respond to 8
weeks of treatment, an additional 4 weeks of treatment may be given.
If there is recurrence of erosive esophagitis or GERD symptoms (eg,
heartburn), additional 4-8 week courses of omeprazole may be
considered.
1.4
Maintenance of Healing of Erosive Esophagitis
(adults and pediatric patients)
PRILOSEC is indicated to maintain healing of erosive esophagitis in
pediatric patients and adults.
Controlled studies do not extend beyond 12 months. [See Clinical
Studies (14.4)]
1.5
Pathological Hypersecretory Conditions (adults)
PRILOSEC is indicated for the long-term treatment of pathological
hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple
endocrine adenomas and systemic mastocytosis) in adults.
2
DOSAGE AND ADMINISTRATION
PRILOSEC Delayed-Release Capsules should be taken before eating.
In the clinical trials, antacids were used concomitantly with
PRILOSEC.
Patients should be informed that the PRILOSEC Delayed-Release
Capsule should be swallowed whole.
For patients unable to swallow an intact capsule, alternative
administration options are available [See Dosage and Administration
(2.8)].
2.1
Short-Term Treatment of Active Duodenal Ulcer
The recommended adult oral dose of PRILOSEC is 20 mg once daily.
Most patients heal within four weeks. Some patients may require an
additional four weeks of therapy.
2.2
H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin) — The
recommended adult oral regimen is PRILOSEC 20 mg plus
clarithromycin 500 mg plus amoxicillin 1000 mg each given twice
daily for 10 days. In patients with an ulcer present at the time of
initiation of therapy, an additional 18 days of PRILOSEC 20 mg once
daily is recommended for ulcer healing and symptom relief.
Dual Therapy (PRILOSEC/clarithromycin) — The recommended
adult oral regimen is PRILOSEC 40 mg once daily plus
clarithromycin 500 mg three times daily for 14 days. In patients with
an ulcer present at the time of initiation of therapy, an additional 14
4
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
days of PRILOSEC 20 mg once daily is recommended for ulcer
healing and symptom relief.
2.3
Gastric Ulcer
The recommended adult oral dose is 40 mg once daily for 4-8 weeks.
2.4
Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients with
symptomatic GERD and no esophageal lesions is 20 mg daily for up
to 4 weeks. The recommended adult oral dose for the treatment of
patients with erosive esophagitis and accompanying symptoms due to
GERD is 20 mg daily for 4 to 8 weeks.
2.5
Maintenance of Healing of Erosive Esophagitis
The recommended adult oral dose is 20 mg daily. [See Clinical
Studies (14.4)]
2.6
Pathological Hypersecretory Conditions
The dosage of PRILOSEC in patients with pathological
hypersecretory conditions varies with the individual patient. The
recommended adult oral starting dose is 60 mg once daily. Doses
should be adjusted to individual patient needs and should continue for
as long as clinically indicated. Doses up to 120 mg three times daily
have been administered. Daily dosages of greater than 80 mg should
be administered in divided doses. Some patients with Zollinger-
Ellison syndrome have been treated continuously with PRILOSEC for
more than 5 years.
2.7
Pediatric Patients
For the treatment of GERD and maintenance of healing of erosive
esophagitis, the recommended daily dose for pediatric patients 1 to
16 years of age is as follows:
Patient Weight
Omeprazole Daily Dose
5 < 10 kg
5 mg
10 < 20 kg
10 mg
> 20 kg
20 mg
On a per kg basis, the doses of omeprazole required to heal erosive
esophagitis in pediatric patients are greater than those for adults.
Alternative administrative options can be used for pediatric patients
unable to swallow an intact capsule [See Dosage and Administration
(2.8)].
2.8
Alternative Administration Options
PRILOSEC is available as a delayed-release capsule or as a delayed-
release oral suspension.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
5
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
3
DOSAGE FORMS AND STRENGTHS
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body.
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body.
6
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body.
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules.
4
CONTRAINDICATIONS
PRILOSEC Delayed-Release Capsules are contraindicated in patients
with known hypersensitivity to substituted benzimidazoles or to any
component of the formulation. Hypersensitivity reactions may include
anaphylaxis,
anaphylactic
shock,
angioedema,
bronchospasm,
interstitial nephritis, and urticaria [See Adverse Reactions (6)].
For information about contraindications of antibacterial agents
(clarithromycin and amoxicillin) indicated in combination with
PRILOSEC, refer to the CONTRAINDICATIONS section of their
package inserts.
5
WARNINGS AND PRECAUTIONS
5.1
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude
the presence of gastric malignancy.
5.2
Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus
biopsies from patients treated long-term with omeprazole.
5.3
Clostridium difficile associated diarrhea
Published observational studies suggest that PPI therapy like
PRILOSEC may be associated with an increased risk of Clostridium
difficile associated diarrhea, especially in hospitalized patients. This
diagnosis should be considered for diarrhea that does not improve
[see Adverse Reactions (6.2)].
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated.
Clostridium diffficile associated diarrhea (CDAD) has been reported
with use of nearly all antibacterial agents. For more information
specific to antibacterial agents (clarithromycin and amoxicillin)
indicated for use in combination with PRILOSEC, refer to
WARNINGS and PRECAUTIONS sections of those package inserts.
5.4
Interaction with Clopidogrel
7
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid concomitant use of PRILOSEC with clopidogrel. Clopidogrel
is a prodrug. Inhibition of platelet aggregation by clopidogrel is
entirely due to an active metabolite. The metabolism of clopidogrel to
its active metabolite can be impaired by use with concomitant
medications, such as omeprazole, that inhibit CYP2C19 activity.
Concomitant use of clopidogrel with 80 mg omeprazole reduces the
pharmacological activity of clopidogrel, even when administered 12
hours apart. When using PRILOSEC, consider alternative anti-platelet
therapy [see Drug Interactions (7.3) and Pharmacokinetics (12.3)].
5.5
Bone Fracture
Several published observational studies suggest that proton pump
inhibitor (PPI) therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as
multiple daily doses, and long-term PPI therapy (a year or longer).
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated. Patients at risk for
osteoporosis-related fractures should be managed according to
established treatment guidelines. [see Dosage and Administration (2)
and Adverse Reactions (6.3)]
5.6
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported
rarely in patients treated with PPIs for at least three months, in most
cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of
hypomagnesemia required magnesium replacement and
discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs
with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), health care professionals may
consider monitoring magnesium levels prior to initiation of PPI
treatment and periodically. [See Adverse Reactions (6.3)]
5.7
Concomitant use of PRILOSEC with St John’s Wort
or rifampin
Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort
or rifampin) can substantially decrease omeprazole concentrations.
[See Drug Interactions (7.3)]. Avoid concomitant use of PRILOSEC
with St John’s Wort or rifampin.
5.8
Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
Serum chromogranin A (CgA) levels increase secondary to drug-
induced decreases in gastric acidity. The increased CgA level may
cause false positive results in diagnostic investigations for
neuroendocrine tumors. Providers should temporarily stop
8
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
omeprazole treatment before assessing CgA levels and consider
repeating the test if initial CgA levels are high. If serial tests are
performed (e.g. for monitoring), the same commercial laboratory
should be used for testing, as reference ranges between tests may
vary.
5.9
Concomitant use of PRILOSEC with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate
(primarily at high dose; see methotrexate prescribing information)
may elevate and prolong serum levels of methotrexate and/or its
metabolite, possibly leading to methotrexate toxicities. In high-dose
methotrexate administration a temporary withdrawal of the PPI may
be considered in some patients. [see Drug Interactions (7. 7)]
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience with PRILOSEC
Monotherapy
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The safety data described below reflects exposure to PRILOSEC
Delayed-Release Capsules in 3096 patients from worldwide clinical
trials (465 patients from US studies and 2,631 patients from
international studies). Indications clinically studied in US trials
included duodenal ulcer, resistant ulcer, and Zollinger-Ellison
syndrome. The international clinical trials were double blind and
open-label in design. The most common adverse reactions reported
(i.e., with an incidence rate ≥ 2%) from PRILOSEC-treated patients
enrolled in these studies included headache (6.9%), abdominal pain
(5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and
flatulence (2.7%).
Additional adverse reactions that were reported with an incidence
≥1% included acid regurgitation (1.9%), upper respiratory infection
(1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia
(1.3%), back pain (1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age
was similar to that in patients 65 years of age or less.
The clinical trial safety profile in pediatric patients who received
PRILOSEC Delayed-Release Capsules was similar to that in adult
patients. Unique to the pediatric population, however, adverse
reactions of the respiratory system were most frequently reported in
both the 1 to <2 and 2 to 16 year age groups (75.0% and 18.5%,
respectively). Similarly, fever was frequently reported in the 1 to 2
year age group (33.0%), and accidental injuries were reported
9
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
frequently in the 2 to 16 year age group (3.8%).[See Use in Specific
Populations (8.4)]
6.2
Clinical Trials Experience with PRILOSEC in
Combination Therapy for H. pylori Eradication
In clinical trials using either dual therapy with PRILOSEC and
clarithromycin, or triple therapy with PRILOSEC, clarithromycin,
and amoxicillin, no adverse reactions unique to these drug
combinations were observed. Adverse reactions observed were
limited to those previously reported with omeprazole, clarithromycin,
or amoxicillin alone.
Dual Therapy (PRILOSEC/clarithromycin)
Adverse reactions observed in controlled clinical trials using
combination therapy with PRILOSEC and clarithromycin (n = 346)
that differed from those previously described for PRILOSEC alone
were taste perversion (15%), tongue discoloration (2%), rhinitis (2%),
pharyngitis (1%) and flu-syndrome (1%). (For more information on
clarithromycin, refer to the clarithromycin prescribing information,
Adverse Reactions section).
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)
The most frequent adverse reactions observed in clinical trials using
combination therapy with PRILOSEC, clarithromycin, and
amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%),
and headache (7%). None of these occurred at a higher frequency
than that reported by patients taking antimicrobial agents alone. (For
more information on clarithromycin or amoxicillin, refer to the
respective prescribing information, Adverse Reactions sections).
6.3 Post-marketing Experience
The following adverse reactions have been identified during post-
approval use of PRILOSEC Delayed-Release Capsules. Because
these reactions are voluntarily reported from a population of uncertain
size, it is not always possible to reliably estimate their actual
frequency or establish a causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions including anaphylaxis,
anaphylactic shock, angioedema, bronchospasm, interstitial nephritis,
urticaria, (see also Skin below); fever; pain; fatigue; malaise;
Cardiovascular: Chest pain or angina, tachycardia, bradycardia,
palpitations, elevated blood pressure, peripheral edema
Endocrine: Gynecomastia
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon,
fecal discoloration, esophageal candidiasis, mucosal atrophy of the
tongue, stomatitis, abdominal swelling, dry mouth, microscopic
colitis. During treatment with omeprazole, gastric fundic gland
polyps have been noted rarely. These polyps are benign and appear to
be reversible when treatment is discontinued.
10
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastroduodenal carcinoids have been reported in patients with ZE
syndrome on long-term treatment with PRILOSEC. This finding is
believed to be a manifestation of the underlying condition, which is
known to be associated with such tumors.
Hepatic: Liver disease including hepatic failure (some fatal), liver
necrosis (some fatal), hepatic encephalopathy hepatocellular disease,
cholestatic disease, mixed hepatitis, jaundice, and elevations of liver
function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
Infections and Infestations: Clostridium difficile associated diarrhea
Metabolism and Nutritional disorders: Hypoglycemia,
hypomagnesemia, hyponatremia, weight gain
Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint
pain, leg pain, bone fracture
Nervous System/Psychiatric: Psychiatric and sleep disturbances
including depression, agitation, aggression, hallucinations, confusion,
insomnia, nervousness, apathy, somnolence, anxiety, and dream
abnormalities; tremors, paresthesia; vertigo
Respiratory: Epistaxis, pharyngeal pain
Skin: Severe generalized skin reactions including toxic epidermal
necrolysis (some fatal), Stevens-Johnson syndrome, and erythema
multiforme; photosensitivity; urticaria; rash; skin inflammation;
pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis
Special Senses: Tinnitus, taste perversion
Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic
neuritis, dry eye syndrome, ocular irritation, blurred vision, double
vision
Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated
serum creatinine, microscopic pyuria, urinary tract infection,
glycosuria, urinary frequency, testicular pain
Hematologic: Agranulocytosis (some fatal), hemolytic anemia,
pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia,
leucocytosis
7
DRUG INTERACTIONS
7.1
Interference with Antiretroviral Therapy
Concomitant use of atazanavir and nelfinavir with proton pump
inhibitors is not recommended. Co-administration of atazanavir with
proton pump inhibitors is expected to substantially decrease
atazanavir plasma concentrations and may result in a loss of
therapeutic effect and the development of drug resistance. Co
administration of saquinavir with proton pump inhibitors is expected
to increase saquinavir concentrations, which may increase toxicity
and require dose reduction.
Omeprazole has been reported to interact with some antiretroviral
drugs. The clinical importance and the mechanisms behind these
interactions are not always known. Increased gastric pH during
omeprazole treatment may change the absorption of the antiretroviral
drug. Other possible interaction mechanisms are via CYP 2C19.
11
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reduced concentrations of atazanavir and nelfinavir
For some antiretroviral drugs, such as atazanavir and nelfinavir,
decreased serum levels have been reported when given together with
omeprazole. Following multiple doses of nelfinavir (1250 mg, twice
daily) and omeprazole (40 mg daily), AUC was decreased by 36%
and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%
respectively for nelfinavir and M8. Following multiple doses of
atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before
atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by
95%. Concomitant administration with omeprazole and drugs such as
atazanavir and nelfinavir is therefore not recommended.
Increased concentrations of saquinavir
For other antiretroviral drugs, such as saquinavir, elevated serum
levels have been reported, with an increase in AUC by 82%, in Cmax
by 75%, and in Cmin by 106%, following multiple dosing of
saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with
omeprazole 40 mg daily co-administered days 11 to 15. Therefore,
clinical and laboratory monitoring for saquinavir toxicity is
recommended during concurrent use with PRILOSEC. Dose
reduction of saquinavir should be considered from the safety
perspective for individual patients.
There are also some antiretroviral drugs of which unchanged serum
levels have been reported when given with omeprazole.
7.2
Drugs for Which Gastric pH Can Affect
Bioavailability
Because of its profound and long lasting inhibition of gastric acid
secretion, it is theoretically possible that omeprazole may interfere
with absorption of drugs where gastric pH is an important
determinant of their bioavailability. Like with other drugs that
decrease the intragastric acidity, the absorption of drugs such as
ketoconazole, ampicillin esters, iron salts and erlotinib can decrease,
while the absorption of drugs such as digoxin can increase during
treatment with omeprazole. Concomitant treatment with omeprazole
(20 mg daily) and digoxin in healthy subjects increased the
bioavailability of digoxin by 10% (30% in two subjects). Therefore,
patients may need to be monitored when digoxin is taken
concomitantly with omeprazole. In the clinical trials, antacids were
used concomitantly with the administration of PRILOSEC.
7.3
Effects on Hepatic Metabolism/Cytochrome P-450
Pathways
Omeprazole can prolong the elimination of diazepam, warfarin and
phenytoin, drugs that are metabolized by oxidation in the liver. There
have been reports of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including omeprazole, and warfarin
concomitantly. Increases in INR and prothrombin time may lead to
12
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
abnormal bleeding and even death. Patients treated with proton pump
inhibitors and warfarin may need to be monitored for increases in
INR and prothrombin time.
Although in normal subjects no interaction with theophylline or
propranolol was found, there have been clinical reports of interaction
with other drugs metabolized via the cytochrome P450 system (e.g.,
cyclosporine, disulfiram, benzodiazepines). Patients should be
monitored to determine if it is necessary to adjust the dosage of these
drugs when taken concomitantly with PRILOSEC.
Concomitant administration of omeprazole and voriconazole (a
combined inhibitor of CYP2C19 and CYP3A4) resulted in more than
doubling of the omeprazole exposure. Dose adjustment of omeprazole
is not normally required. However, in patients with Zollinger-Ellison
syndrome, who may require higher doses up to 240 mg/day, dose
adjustment may be considered. When voriconazole (400 mg Q12h x 1
day, then 200 mg x 6 days) was given with omeprazole (40 mg once
daily x 7 days) to healthy subjects, it significantly increased the
steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times
(90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as
compared to when omeprazole was given without voriconazole.
Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in
doses of 40 mg daily for one week to 20 healthy subjects in cross
over study, increased Cmax and AUC of cilostazol by 18% and 26%
respectively. Cmax and AUC of one of its active metabolites, 3,4
dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were
increased by 29% and 69% respectively. Co-administration of
cilostazol with omeprazole is expected to increase concentrations of
cilostazol and its above mentioned active metabolite. Therefore a
dose reduction of cilostazol from 100 mg twice daily to 50 mg twice
daily should be considered.
Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin)
may lead to decreased omeprazole serum levels. In a cross-over study
in 12 healthy male subjects, St John’s wort (300 mg three times daily
for 14 days), an inducer of CYP3A4, decreased the systemic exposure
of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC
decreased by 37.5% and 37.9%, respectively) and extensive
metabolisers (Cmax and AUC decreased by 49.6% and 43.9%,
respectively). Avoid concomitant use of St. John’s Wort or rifampin
with omeprazole.
Clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is
metabolized to its active metabolite in part by CYP2C19.
Concomitant use of omeprazole 80 mg results in reduced plasma
concentrations of the active metabolite of clopidogrel and a reduction
in platelet inhibition. Avoid concomitant administration of
13
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRILOSEC with clopidogrel. When using PRILOSEC, consider use
of alternative anti-platelet therapy [see Pharmacokinetics (12.3)].
There are no adequate combination studies of a lower dose of
omeprazole or a higher dose of clopidogrel in comparison with the
approved dose of clopidogrel.
7.4
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may
increase the serum levels of tacrolimus.
7.5
Interactions with Investigations of Neuroendocrine
Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin
like cell hyperplasia and increased Chromogranin A levels which may
interfere with investigations for neuroendocrine tumors. [see
Warnings and Precautions (5.8) and Clinical Pharmacology (12)].
7.6
Combination Therapy with Clarithromycin
Concomitant administration of clarithromycin with other drugs can
lead to serious adverse reactions due to drug interactions [see
Warnings and Precautions in prescribing information for
clarithromycin]. Because of these drug interactions, clarithromycin is
contraindicated for co-administration with certain drugs [see
Contraindications in prescribing information for clarithromycin].
7. 7 Methotrexate
Case reports, published population pharmacokinetic studies, and
retrospective analyses suggest that concomitant administration of
PPIs and methotrexate (primarily at high dose; see methotrexate
prescribing information) may elevate and prolong serum levels of
methotrexate and/or its metabolite hydroxymethotrexate. However,
no formal drug interaction studies of methotrexate with PPIs have
been conducted [see Warnings and Precautions (5.9)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with PRILOSEC in
pregnant women. Available epidemiologic data fail to demonstrate an
increased risk of major congenital malformations or other adverse
pregnancy outcomes with first trimester omeprazole use.
Reproduction studies in rats and rabbits resulted in dose-dependent
embryolethality at omeprazole doses that were approximately 5.5 –
56 times higher than the human dose. PRILOSEC should be used
during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
14
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Human Data
Four epidemiological studies compared the frequency of congenital
abnormalities among infants born to women who used omeprazole
during pregnancy with the frequency of abnormalities among infants
of women exposed to H2-receptor antagonists or other controls.
A population-based retrospective cohort epidemiological study from
the Swedish Medical Birth Registry, covering approximately 99% of
pregnancies, from 1995-99, reported on 955 infants (824 exposed
during the first trimester with 39 of these exposed beyond first
trimester, and 131 exposed after the first trimester) whose mothers
used omeprazole during pregnancy. The number of infants exposed in
utero to omeprazole that had any malformation, low birth weight, low
Apgar score, or hospitalization was similar to the number observed in
this population. The number of infants born with ventricular septal
defects and the number of stillborn infants was slightly higher in the
omeprazole-exposed infants than the expected number in this
population.
A population-based retrospective cohort study covering all live births
in Denmark from 1996-2009, reported on 1,800 live births whose
mothers used omeprazole during the first trimester of pregnancy and
837, 317 live births whose mothers did not use any proton pump
inhibitor. The overall rate of birth defects in infants born to mothers
with first trimester exposure to omeprazole was 2.9% and 2.6% in
infants born to mothers not exposed to any proton pump inhibitor
during the first trimester.
A retrospective cohort study reported on 689 pregnant women
exposed to either H2-blockers or omeprazole in the first trimester (134
exposed to omeprazole) and 1,572 pregnant women unexposed to
either during the first trimester. The overall malformation rate in
offspring born to mothers with first trimester exposure to omeprazole,
an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1%
respectively.
A small prospective observational cohort study followed 113 women
exposed to omeprazole during pregnancy (89% first trimester
exposures). The reported rate of major congenital malformations was
4% in the omeprazole group, 2% in controls exposed to non
teratogens, and 2.8% in disease-paired controls. Rates of spontaneous
and elective abortions, preterm deliveries, gestational age at delivery,
and mean birth weight were similar among the groups.
Several studies have reported no apparent adverse short-term effects
on the infant when single dose oral or intravenous omeprazole was
administered to over 200 pregnant women as premedication for
cesarean section under general anesthesia.
15
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Animal Data
Reproductive studies conducted with omeprazole in rats at oral doses
up to 138 mg/kg/day (about 56 times the human dose on a body
surface area basis) and in rabbits at doses up to 69 mg/kg/day (about
56 times the human dose on a body surface area basis) did not
disclose any evidence for a teratogenic potential of omeprazole. In
rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about
5.5 to 56 times the human dose on a body surface area basis)
produced dose-related increases in embryo-lethality, fetal resorptions,
and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity
and postnatal developmental toxicity were observed in offspring
resulting from parents treated with omeprazole at 13.8 to 138.0
mg/kg/day (about 5.6 to 56 times the human doses on a body surface
area basis).
8.3
Nursing Mothers
Omeprazole is present in human milk. Omeprazole concentrations
were measured in breast milk of a woman following oral
administration of 20 mg. The peak concentration of omeprazole in
breast milk was less than 7% of the peak serum concentration. This
concentration would correspond to 0.004 mg of omeprazole in 200
mL of milk. Caution should be exercised when PRILOSEC is
administered to a nursing woman.
8.4
Pediatric Use
Use of PRILOSEC in pediatric and adolescent patients 1 to 16 years
of age for the treatment of GERD and maintenance of healing of
erosive esophagitis is supported by a) extrapolation of results from
adequate and well-controlled studies that supported the approval of
PRILOSEC for adults, and b) safety and pharmacokinetic studies
performed in pediatric and adolescent patients. [See Clinical
Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic
information (12.3) and Dosage and Administration (2), Adverse
Reactions (6.1) and Clinical Studies, (14.6)]. The safety and
effectiveness of PRILOSEC for the treatment of GERD in patients <1
year of age have not been established. The safety and effectiveness of
PRILOSEC for other pediatric uses have not been established.
8.5
Geriatric Use
Omeprazole was administered to over 2000 elderly individuals (≥ 65
years of age) in clinical trials in the U.S. and Europe. There were no
differences in safety and effectiveness between the elderly and
younger subjects. Other reported clinical experience has not
identified differences in response between the elderly and younger
subjects, but greater sensitivity of some older individuals cannot be
ruled out.
Pharmacokinetic studies have shown the elimination rate was
somewhat decreased in the elderly and bioavailability was increased.
The plasma clearance of omeprazole was 250 mL/min (about half that
16
Reference ID: 3308075
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of young volunteers) and its plasma half-life averaged one hour, about
twice that of young healthy volunteers. However, no dosage
adjustment is necessary in the elderly. [See Clinical Pharmacology
(12.3)]
8.6
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
8.7
Renal Impairment
No dosage reduction is necessary. [See Clinical Pharmacology
(12.3)]
8.8
Asian Population
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. [See Clinical Pharmacology (12.3)]
10
OVERDOSAGE
Reports have been received of overdosage with omeprazole in
humans. Doses ranged up to 2400 mg (120 times the usual
recommended clinical dose). Manifestations were variable, but
included confusion, drowsiness, blurred vision, tachycardia, nausea,
vomiting, diaphoresis, flushing, headache, dry mouth, and other
adverse reactions similar to those seen in normal clinical experience.
[See Adverse Reactions (6)] Symptoms were transient, and no serious
clinical outcome has been reported when PRILOSEC was taken
alone. No specific antidote for omeprazole overdosage is known.
Omeprazole is extensively protein bound and is, therefore, not readily
dialyzable. In the event of overdosage, treatment should be
symptomatic and supportive.
As with the management of any overdose, the possibility of multiple
drug ingestion should be considered. For current information on
treatment of any drug overdose, contact a Poison Control Center at 1
800-222-1222.
Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were
lethal to mice, rats, and dogs, respectively. Animals given these doses
showed sedation, ptosis, tremors, convulsions, and decreased activity,
body temperature, and respiratory rate and increased depth of
respiration.
11
DESCRIPTION
The active ingredient in PRILOSEC (omeprazole) Delayed-Release
Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy
3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a
compound that inhibits gastric acid secretion. Its empirical formula is
C17H19N3O3S, with a molecular weight of 345.42. The structural
formula is:
17
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structural formula
Omeprazole is a white to off-white crystalline powder that melts with
decomposition at about 155°C. It is a weak base, freely soluble in
ethanol and methanol, and slightly soluble in acetone and isopropanol
and very slightly soluble in water. The stability of omeprazole is a
function of pH; it is rapidly degraded in acid media, but has
acceptable stability under alkaline conditions.
The active ingredient in PRILOSEC (omeprazole magnesium) for
Delayed Release Oral Suspension, is 5-Methoxy-2-[[(4-methoxy-3,5
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium
salt (2:1)
Omeprazole magnesium is a white to off white powder with a melting
point with degradation at 200°C. The salt is slightly soluble (0.25
mg/mL) in water at 25°C, and it is soluble in methanol. The half-life
is highly pH dependent.
The empirical formula for omeprazole magnesium is (C17H18N3O3S)2
Mg, the molecular weight is 713.12 and the structural formula is: structural formula
PRILOSEC is supplied as delayed-release capsules for oral
administration. Each delayed-release capsule contains either 10 mg,
20 mg or 40 mg of omeprazole in the form of enteric-coated granules
with the following inactive ingredients: cellulose, disodium hydrogen
phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate and other ingredients. The capsule shells have
the following inactive ingredients: gelatin-NF, FD&C Blue #1,
FD&C Red #40, D&C Red #28, titanium dioxide, synthetic black iron
oxide, isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7
Calcium Lake, and, in addition, the 10 mg and 40 mg capsule shells
also contain D&C Yellow #10.
Each packet of PRILOSEC For Delayed-Release Oral Suspension
contains either 2.8 mg or 11.2 mg of omeprazole magnesium
(equivalent to 2.5 mg or 10 mg of omeprazole), in the form of enteric
coated granules with the following inactive ingredients: glyceryl
18
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monostearate, hydroxypropyl cellulose, hypromellose, magnesium
stearate, methacrylic acid copolymer C, polysorbate, sugar spheres,
talc, and triethyl citrate, and also inactive granules. The inactive
granules are composed of the following ingredients: citric acid,
crospovidone, dextrose, hydroxypropyl cellulose, iron oxide and
xantham gum. The omeprazole granules and inactive granules are
constituted with water to form a suspension and are given by oral,
nasogastric or direct gastric administration.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Omeprazole belongs to a class of antisecretory compounds, the
substituted benzimidazoles, that suppress gastric acid secretion by
specific inhibition of the H+/K+ ATPase enzyme system at the
secretory surface of the gastric parietal cell. Because this enzyme
system is regarded as the acid (proton) pump within the gastric
mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect
is dose-related and leads to inhibition of both basal and stimulated
acid secretion irrespective of the stimulus. Animal studies indicate
that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
12.2 Pharmacodynamics
Antisecretory Activity
After oral administration, the onset of the antisecretory effect of
omeprazole occurs within one hour, with the maximum effect
occurring within two hours. Inhibition of secretion is about 50% of
maximum at 24 hours and the duration of inhibition lasts up to 72
hours. The antisecretory effect thus lasts far longer than would be
expected from the very short (less than one hour) plasma half-life,
apparently due to prolonged binding to the parietal H+/K+ ATPase
enzyme. When the drug is discontinued, secretory activity returns
gradually, over 3 to 5 days. The inhibitory effect of omeprazole on
acid secretion increases with repeated once-daily dosing, reaching a
plateau after four days.
Results from numerous studies of the antisecretory effect of multiple
doses of 20 mg and 40 mg of omeprazole in normal volunteers and
patients are shown below. The “max” value represents determinations
at a time of maximum effect (2-6 hours after dosing), while “min”
values are those 24 hours after the last dose of omeprazole.
Table 1
Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole
After Multiple Daily Dosing
Omeprazole
Omeprazole
Parameter
20 mg
40 mg
19
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% Decrease in Basal Acid
Output
Max
78*
Min
58-80
Max
94*
Min
80-93
% Decrease in Peak Acid
Output
79*
50-59
88*
62-68
% Decrease in 24-hr.
Intragastric Acidity
80-97
92-94
*Single Studies
Single daily oral doses of omeprazole ranging from a dose of 10 mg
to 40 mg have produced 100% inhibition of 24-hour intragastric
acidity in some patients.
Serum Gastrin Effects
In studies involving more than 200 patients, serum gastrin levels
increased during the first 1 to 2 weeks of once-daily administration of
therapeutic doses of omeprazole in parallel with inhibition of acid
secretion. No further increase in serum gastrin occurred with
continued treatment. In comparison with histamine H2-receptor
antagonists, the median increases produced by 20 mg doses of
omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase).
Gastrin values returned to pretreatment levels, usually within 1 to 2
weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and
increased serum Chromogranin A (CgA) levels. The increased CgA
levels may cause false positive results in diagnostic investigations for
neuroendocrine tumors.
Enterochromaffin-like (ECL) Cell Effects
Human gastric biopsy specimens have been obtained from more than
3000 patients treated with omeprazole in long-term clinical trials. The
incidence of ECL cell hyperplasia in these studies increased with
time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia
has been found in these patients. [See Clinical Pharmacology (12)]
However, these studies are of insufficient duration and size to rule out
the possible influence of long-term administration of omeprazole on
the development of any premalignant or malignant conditions.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and
respiratory systems have not been found to date. Omeprazole, given
in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid
function, carbohydrate metabolism, or circulating levels of
parathyroid hormone, cortisol, estradiol, testosterone, prolactin,
cholecystokinin or secretin.
No effect on gastric emptying of the solid and liquid components of a
test meal was demonstrated after a single dose of omeprazole 90 mg.
In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had
no effect on intrinsic factor secretion. No systematic dose-dependent
20
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effect has been observed on basal or stimulated pepsin output in
humans.
However, when intragastric pH is maintained at 4.0 or above, basal
pepsin output is low, and pepsin activity is decreased.
As do other agents that elevate intragastric pH, omeprazole
administered for 14 days in healthy subjects produced a significant
increase in the intragastric concentrations of viable bacteria. The
pattern of the bacterial species was unchanged from that commonly
found in saliva. All changes resolved within three days of stopping
treatment.
The course of Barrett’s esophagus in 106 patients was evaluated in a
U.S. double-blind controlled study of PRILOSEC 40 mg twice daily
for 12 months followed by 20 mg twice daily for 12 months or
ranitidine 300 mg twice daily for 24 months. No clinically significant
impact on Barrett’s mucosa by antisecretory therapy was observed.
Although neosquamous epithelium developed during antisecretory
therapy, complete elimination of Barrett’s mucosa was not achieved.
No significant difference was observed between treatment groups in
development of dysplasia in Barrett’s mucosa and no patient
developed esophageal carcinoma during treatment. No significant
differences between treatment groups were observed in development
of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal
metaplasia, or colon polyps exceeding 3 mm in diameter [See Clinical
Pharmacology (12)].
12.3 Pharmacokinetics
Absorption
PRILOSEC Delayed-Release Capsules contain an enteric-coated
granule formulation of omeprazole (because omeprazole is acid-
labile), so that absorption of omeprazole begins only after the
granules leave the stomach. Absorption is rapid, with peak plasma
levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma
concentrations of omeprazole and AUC are approximately
proportional to doses up to 40 mg, but because of a saturable first-
pass effect, a greater than linear response in peak plasma
concentration and AUC occurs with doses greater than 40 mg.
Absolute bioavailability (compared with intravenous administration)
is about 30-40% at doses of 20-40 mg, due in large part to
presystemic metabolism. In healthy subjects the plasma half-life is 0.5
to 1 hour, and the total body clearance is 500-600 mL/min.
Based on a relative bioavailability study, the AUC and Cmax of
PRILOSEC (omeprazole magnesium) for Delayed-Release Oral
Suspension were 87% and 88% of those for PRILOSEC Delayed-
Release Capsules, respectively.
21
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The bioavailability of omeprazole increases slightly upon repeated
administration of PRILOSEC Delayed-Release Capsules.
PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when
administered with and without applesauce. However, PRILOSEC
Delayed-Release Capsule 20 mg was not bioequivalent when
administered with and without applesauce. When administered with
applesauce, a mean 25% reduction in Cmax was observed without a
significant change in AUC for PRILOSEC Delayed-Release Capsule
20 mg. The clinical relevance of this finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450
(CYP) enzyme system.
Excretion
Following single dose oral administration of a buffered solution of
omeprazole, little if any unchanged drug was excreted in urine. The
majority of the dose (about 77%) was eliminated in urine as at least
six metabolites. Two were identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was
recoverable in feces. This implies a significant biliary excretion of the
metabolites of omeprazole. Three metabolites have been identified in
plasma — the sulfide and sulfone derivatives of omeprazole, and
hydroxyomeprazole. These metabolites have very little or no
antisecretory activity.
Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with
clarithromycin 500 mg every 8 hours to healthy adult male subjects.
The steady state plasma concentrations of omeprazole were increased
(Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34%
respectively) by the concomitant administration of clarithromycin.
The observed increases in omeprazole plasma concentration were
associated with the following pharmacological effects. The mean 24
hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin
were increased by the concomitant administration of omeprazole. For
clarithromycin, the mean Cmax was 10% greater, the mean Cmin was
27% greater, and the mean AUC0-8 was 15% greater when
clarithromycin was administered with omeprazole than when
clarithromycin was administered alone. Similar results were seen for
14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean
Cmin was 57% greater, and the mean AUC0-8 was 45% greater.
22
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Clarithromycin concentrations in the gastric tissue and mucus were
also increased by concomitant administration of omeprazole.
Table 2
Clarithromycin Tissue Concentrations
2 hours after Dose
1
Clarithromycin +
Tissue
Clarithromycin
Omeprazole
Antrum
10.48 ± 2.01 (n = 5)
19.96 ± 4.71 (n = 5)
Fundus
20.81 ± 7.64 (n = 5)
24.25 ± 6.37 (n = 5)
Mucus
4.15 ± 7.74 (n = 4)
39.29 ± 32.79 (n = 4)
1Mean ± SD (μg/g)
Concomitant Use with Clopidogrel
In a crossover clinical study, 72 healthy subjects were administered
clopidogrel (300 mg loading dose followed by 75 mg per day) alone
and with omeprazole (80 mg at the same time as clopidogrel) for 5
days. The exposure to the active metabolite of clopidogrel was
decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and
omeprazole were administered together.
Results from another crossover study in healthy subjects showed a
similar pharmacokinetic interaction between clopidogrel (300 mg
loading dose/75 mg daily maintenance dose) and omeprazole 80 mg
daily when co-administered for 30 days. Exposure to the active
metabolite of clopidogrel was reduced by 41% to 46% over this time
period.
In another study, 72 healthy subjects were given the same doses of
clopidogrel and 80 mg omeprazole but the drugs were administered
12 hours apart; the results were similar, indicating that administering
clopidogrel and omeprazole at different times does not prevent their
interaction.
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the
elderly, and bioavailability was increased. Omeprazole was 76%
bioavailable when a single 40 mg oral dose of omeprazole (buffered
solution) was administered to healthy elderly volunteers, versus 58%
in young volunteers given the same dose. Nearly 70% of the dose was
recovered in urine as metabolites of omeprazole and no unchanged
drug was detected. The plasma clearance of omeprazole was 250
mL/min (about half that of young volunteers) and its plasma half-life
averaged one hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in
pediatric patients 2 to 16 years of age:
23
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Table 3
Pharmacokinetic Parameters of Omeprazole Following Single
and Repeated Oral Administration in Pediatric Populations
Compared with Adults
Single or
Children†
Children†
Adults‡
Repeated
< 20 kg
> 20 kg
(mean
Oral Dosing
2-5 years
6-16
76 kg)
/Parameter
10 mg
years
23-29
20 mg
years
(n=12)
Single Dosing
Cmax *
288
495
668
(ng/mL)
(n=10)
(n=49)
AUC*
511
1140
1220
(ng h/mL)
(n=7)
(n=32)
Repeated Dosing
Cmax *
539
851
1458
(ng/mL)
(n=4)
(n=32)
AUC*
1179
2276
3352
(ng h/mL)
(n=2)
(n=23)
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
†Data from single and repeated dose studies
‡Data from a single and repeated dose study
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children
(2 to 5 years of age) have lower AUCs than children 6 to 16 years of
age or adults; AUCs of the latter two groups did not differ. [See
Dosage and Administration (2)]
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased
to approximately 100% compared with an I.V. dose, reflecting
decreased first-pass effect, and the plasma half-life of the drug
increased to nearly 3 hours compared with the half-life in normals of
0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a
value of 500-600 mL/min in normal subjects. Dose reduction,
particularly where maintenance of healing of erosive esophagitis is
indicated, for the hepatically impaired should be considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance
ranged between 10 and 62 mL/min/1.73 m2, the disposition of
omeprazole was very similar to that in healthy volunteers, although
there was a slight increase in bioavailability. Because urinary
excretion is a primary route of excretion of omeprazole metabolites,
their elimination slowed in proportion to the decreased creatinine
clearance. No dose reduction is necessary in patients with renal
impairment.
24
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Asian Population
In pharmacokinetic studies of single 20 mg omeprazole doses, an
increase in AUC of approximately four-fold was noted in Asian
subjects compared with Caucasians. Dose reduction, particularly
where maintenance of healing of erosive esophagitis is indicated, for
Asian subjects should be considered.
12.4 Microbiology
Omeprazole and clarithromycin dual therapy and omeprazole,
clarithromycin and amoxicillin triple therapy have been shown to be
active against most strains of Helicobacter pylori in vitro and in
clinical infections as described in the Indications and Usage section
(1.1).
Helicobacter
Helicobacter pylori- Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the
omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3%
(41/439) in omeprazole/clarithromycin/amoxicillin triple therapy
studies (1, 2, and 3).
Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were
found in 99.3% (436/439) of the patients in the
omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2,
and 3). Amoxicillin pretreatment minimum inhibitory concentrations
(MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of
whom were in the clarithromycin and amoxicillin study arm. One
patient had an unconfirmed pretreatment amoxicillin minimum
inhibitory concentration (MIC) of > 256 µg/mL by Etest® .
Table 4
Clarithromycin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a
Clarithromycin Pretreatment Results
Clarithromycin Post-treatment Results
H. pylori negative –
eradicated
H. pylori positive – not eradicated
Post-treatment susceptibility results
S b
I b
R b
No MIC
Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed
by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5)
Susceptible b
108
72
1
26
9
Intermediate b
1
1
Resistant b
4
4
Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice
daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies
1, 2)
Susceptible b
171
153
7
3
8
Intermediateb
Resistant b
14
4
1
6
3
aIncludes only patients with pretreatment clarithromycin susceptibility test results
bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC 0.5 – 1.0 µg/mL, Resistant (R) MIC ≥ 2
μg/mL
25
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Patients not eradicated of H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy or
omeprazole/clarithromycin dual therapy will likely have
clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with
clarithromycin resistant H. pylori should not be treated with any of
the following: omeprazole/clarithromycin dual therapy,
omeprazole/clarithromycin/amoxicillin triple therapy, or other
regimens which include clarithromycin as the sole antimicrobial
agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
In the triple therapy clinical trials, 84.9% (157/185) of the patients in
the omeprazole/clarithromycin/amoxicillin treatment group who had
pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were
eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment
susceptibility test results and 17 had post-treatment H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed
triple therapy also had post-treatment H. pylori isolates with
clarithromycin resistant MICs.
Susceptibility Test for Helicobacter pylori
For susceptibility testing information about Helicobacter pylori, see
Microbiology section in prescribing information for clarithromycin
and amoxicillin.
Effects on Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including proton pump
inhibitors, increases gastric counts of bacteria normally present in the
gastrointestinal tract. Treatment with proton pump inhibitors may
lead to slightly increased risk of gastrointestinal infections such as
Salmonella and Campylobacter and, in hospitalized patients, possibly
also Clostridium difficile.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily
doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57
times a human dose of 20 mg/day, as expressed on a body surface
area basis) produced gastric ECL cell carcinoids in a dose-related
manner in both male and female rats; the incidence of this effect was
markedly higher in female rats, which had higher blood levels of
omeprazole. Gastric carcinoids seldom occur in the untreated rat. In
addition, ECL cell hyperplasia was present in all treated groups of
both sexes. In one of these studies, female rats were treated with 13.8
mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day,
based on body surface area) for one year, and then followed for an
additional year without the drug. No carcinoids were seen in these
26
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
rats. An increased incidence of treatment-related ECL cell hyperplasia
was observed at the end of one year (94% treated vs 10% controls).
By the second year the difference between treated and control rats
was much smaller (46% vs 26%) but still showed more hyperplasia in
the treated group. Gastric adenocarcinoma was seen in one rat (2%).
No similar tumor was seen in male or female rats treated for two
years. For this strain of rat no similar tumor has been noted
historically, but a finding involving only one tumor is difficult to
interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain
astrocytomas were found in a small number of males that received
omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to
6.5 times the human dose on a body surface area basis). No
astrocytomas were observed in female rats in this study. In a 2-year
carcinogenicity study in Sprague-Dawley rats, no astrocytomas were
found in males or females at the high dose of 140.8 mg/kg/day (about
57 times the human dose on a body surface area basis). A 78-week
mouse carcinogenicity study of omeprazole did not show increased
tumor occurrence, but the study was not conclusive. A 26-week p53
(+/-) transgenic mouse carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an in vitro human
lymphocyte chromosomal aberration assay, in one of two in vivo
mouse micronucleus tests, and in an in vivo bone marrow cell
chromosomal aberration assay. Omeprazole was negative in the in
vitro Ames test, an in vitro mouse lymphoma cell forward mutation
assay, and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times
the human dose on a body surface area basis) was found to have no
effect on fertility and reproductive performance.
In 24-month carcinogenicity studies in rats, a dose-related significant
increase in gastric carcinoid tumors and ECL cell hyperplasia was
observed in both male and female animals [See Warnings and
Precautions (5)]. Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other proton
pump inhibitors or high doses of H2-receptor antagonists.
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
Active Duodenal Ulcer— In a multicenter, double-blind, placebo-
controlled study of 147 patients with endoscopically documented
duodenal ulcer, the percentage of patients healed (per protocol) at 2
and 4 weeks was significantly higher with PRILOSEC 20 mg once
daily than with placebo (p ≤ 0.01).
27
Reference ID: 3308075
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Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Placebo
20 mg a.m.
a.m.
Week 2
(n = 99)
* 41
(n = 48)
13
Week 4
* 75
27
*(p < 0.01)
Complete daytime and nighttime pain relief occurred significantly
faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in
patients treated with placebo. At the end of the study, significantly
more patients who had received PRILOSEC had complete relief of
daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).
In a multicenter, double-blind study of 293 patients with
endoscopically documented duodenal ulcer, the percentage of patients
healed (per protocol) at 4 weeks was significantly higher with
PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p <
0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg a.m.
150 mg twice daily
(n = 145)
(n = 148)
Week 2
42
34
Week 4
*82
63
*(p < 0.01)
Healing occurred significantly faster in patients treated with
PRILOSEC than in those treated with ranitidine 150 mg b.i.d. (p <
0.01).
In a foreign multinational randomized, double-blind study of 105
patients with endoscopically documented duodenal ulcer, 20 mg and
40 mg of PRILOSEC were compared with 150 mg b.i.d. of ranitidine
at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were
statistically superior (per protocol) to ranitidine, but 40 mg was not
superior to 20 mg of PRILOSEC, and at 8 weeks there was no
significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg
40 mg
150 mg twice
(n = 34)
(n = 36)
daily
(n = 35)
Week 2
*83
*83
53
Week 4
Week 8
*97
100
*100
100
82
94
*(p < 0.01)
28
Reference ID: 3308075
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H. pylori Eradication in Patients with Duodenal Ulcer
Disease
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)— Three
U.S., randomized, double-blind clinical studies in patients with H.
pylori infection and duodenal ulcer disease (n = 558) compared
PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin
plus amoxicillin. Two studies (1 and 2) were conducted in patients
with an active duodenal ulcer, and the other study (3) was conducted
in patients with a history of a duodenal ulcer in the past 5 years but
without an ulcer present at the time of enrollment. The dose regimen
in the studies was PRILOSEC 20 mg twice daily plus clarithromycin
500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or
clarithromycin 500 mg. twice daily plus amoxicillin 1 g twice daily
for 10 days. In studies 1 and 2, patients who took the omeprazole
regimen also received an additional 18 days of PRILOSEC 20 mg
once daily. Endpoints studied were eradication of H. pylori and
duodenal ulcer healing (studies 1 and 2 only). H. pylori status was
determined by CLOtest®, histology and culture in all three studies.
For a given patient, H. pylori was considered eradicated if at least two
of these tests were negative, and none was positive.
The combination of omeprazole plus clarithromycin plus amoxicillin
was effective in eradicating H. pylori.
Table 5
Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
% of Patients Cured [95% Confidence Interval]
PRILOSEC +clarithromycin
Clarithromycin +amoxicillin
+amoxicillin
Per-Protocol †
Intent-to-Treat ‡
Per-Protocol † Intent-to-Treat ‡
Study 1
*77 [64, 86]
(n = 64)
*69 [57, 79]
(n = 80)
43 [31, 56]
(n = 67)
37 [27, 48]
(n = 84)
Study 2
*78 [67, 88]
(n = 65)
*73 [61, 82]
(n = 77)
41 [29, 54]
(n = 68)
36 [26, 47]
(n = 83)
Study 3
*90 [80, 96]
(n = 69)
*83 [74, 91]
(n = 84)
33 [24, 44]
(n = 93)
32 [23, 42]
(n = 99)
† Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer
within 5 years, study 3) and H. pylori infection at baseline defined as
at least two of three positive endoscopic tests from CLOtest® ,
histology, and/or culture. Patients were included in the analysis if
they completed the study. Additionally, if patients dropped out of
the study due to an adverse event related to the study drug, they were
included in the analysis as failures of therapy. The impact of
eradication on ulcer recurrence has not been assessed in patients with
a past history of ulcer.
‡ Patients were included in the analysis if they had documented
H. pylori infection at baseline and had confirmed duodenal ulcer
disease. All dropouts were included as failures of therapy.
* (p < 0.05) versus clarithromycin plus amoxicillin.
29
Reference ID: 3308075
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Dual Therapy (PRILOSEC/clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7)
evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg
three times daily for 14 days, followed by PRILOSEC 20 mg once
daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study
6) for an additional 14 days in patients with active duodenal ulcer
associated with H. pylori. Studies 4 and 5 were conducted in the U.S.
and Canada and enrolled 242 and 256 patients, respectively. H. pylori
infection and duodenal ulcer were confirmed in 219 patients in Study
4 and 228 patients in Study 5. These studies compared the
combination regimen to PRILOSEC and clarithromycin
monotherapies. Studies 6 and 7 were conducted in Europe and
enrolled 154 and 215 patients, respectively. H. pylori infection and
duodenal ulcer were confirmed in 148 patients in Study 6 and 208
patients in Study 7. These studies compared the combination regimen
with omeprazole monotherapy. The results for the efficacy analyses
for these studies are described below. H. pylori eradication was
defined as no positive test (culture or histology) at 4 weeks following
the end of treatment, and two negative tests were required to be
considered eradicated of H. pylori. In the per-protocol analysis, the
following patients were excluded: dropouts, patients with missing H.
pylori tests post-treatment, and patients that were not assessed for H.
pylori eradication because they were found to have an ulcer at the end
of treatment.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori.
Table 6
H. pylori Eradication Rates (Per-Protocol Analysis
at 4 to 6 Weeks)
% of Patients Cured [95% Confidence Interval]
PRILOSEC +
Clarithromycin
PRILOSEC
Clarithromycin
U.S. Studies
Study 4
74 [60, 85] †‡
0 [0, 7]
31 [18, 47]
(n = 53)
(n = 54)
(n = 42)
Study 5
64 [51, 76] †‡
(n = 61)
0 [0, 6]
(n = 59)
39 [24, 55]
(n = 44)
Non U.S. Studies
Study 6
83 [71, 92] ‡
(n = 60)
1 [0, 7]
(n = 74)
N/A
Study 7
74 [64, 83] ‡
1 [0, 6]
N/A
(n = 86)
(n = 90)
†Statistically significantly higher than clarithromycin
monotherapy (p < 0.05)
‡Statistically significantly higher than omeprazole
monotherapy (p < 0.05)
Ulcer healing was not significantly different when clarithromycin was
added to omeprazole therapy compared with omeprazole therapy
alone.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori and reduced duodenal ulcer recurrence.
30
Reference ID: 3308075
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Table 7
Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status
% of Patients with Ulcer Recurrence
H. pylori eradicated#
H. pylori not eradicated#
U.S. Studies †
6 months post-treatment
Study 4
*35
60
(n = 49)
(n = 88)
Study 5
*8
60
(n = 53)
(n = 106)
Non U.S. Studies ‡
6 months post-treatment
Study 6
*5
46
(n = 43)
(n = 78)
Study 7
*6
43
(n = 53)
(n = 107)
12 months post-treatment
Study 6
*5
68
(n = 39)
(n = 71)
#H. pylori eradication status assessed at same time point as ulcer recurrence
†Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment
arms
‡Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
*(p < 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori
eradicated
14.2 Gastric Ulcer
In a U.S. multicenter, double-blind, study of omeprazole 40 mg once
daily, 20 mg once daily, and placebo in 520 patients with
endoscopically diagnosed gastric ulcer, the following results were
obtained.
Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC
PRILOSEC
20 mg once daily
40 mg once daily
Placebo
(n = 202)
(n = 214)
(n = 104)
Week 4
47.5**
55.6**
30.8
Week 8
48.1
74.8**
82.7**,+
**(p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
+(p < 0.05) PRILOSEC 40 mg versus 20 mg
For the stratified groups of patients with ulcer size less than or equal
to 1 cm, no difference in healing rates between 40 mg and 20 mg was
detected at either 4 or 8 weeks. For patients with ulcer size greater
than 1 cm, 40 mg was significantly more effective than 20 mg at 8
weeks.
In a foreign, multinational, double-blind study of 602 patients with
endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily,
20 mg once daily, and ranitidine 150 mg twice a day were evaluated.
31
Reference ID: 3308075
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Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
40 mg once daily
150 mg twice daily
(n = 200)
(n = 187)
(n = 199)
Week 4
63.5
56.3
78.1**,++
Week 8
81.5
78.4
91.4**,++
** (p < 0.01) PRILOSEC 40 mg versus ranitidine
++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
14.3 Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo-controlled study was conducted in Scandinavia to compare
the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4
weeks in the treatment of heartburn and other symptoms in GERD
patients without erosive esophagitis. Results are shown below.
% Successful Symptomatic Outcomea
PRILOSEC
PRILOSEC
Placebo
20 mg a.m.
10 mg a.m.
a.m.
All patients
46*,†
31†
13
(n = 105)
(n = 205)
(n = 199)
Patients with
14
56*,†
36†
confirmed GERD
(n = 59)
(n = 115)
(n = 109)
aDefined as complete resolution of heartburn
*(p < 0.005) versus 10 mg
†(p < 0.005) versus placebo
14.4 Erosive Esophagitis
In a U.S. multicenter double-blind placebo controlled study of 20 mg
or 40 mg of PRILOSEC Delayed-Release Capsules in patients with
symptoms of GERD and endoscopically diagnosed erosive
esophagitis of grade 2 or above, the percentage healing rates (per
protocol) were as follows:
20 mg PRILOSEC
40 mg PRILOSEC
Placebo
Week
(n = 83)
(n = 87)
(n = 43)
4
39**
45**
7
8
14
74**
75**
** (p < 0.01) PRILOSEC versus placebo.
In this study, the 40 mg dose was not superior to the 20 mg dose of
PRILOSEC in the percentage healing rate. Other controlled clinical
trials have also shown that PRILOSEC is effective in severe GERD.
In comparisons with histamine H2-receptor antagonists in patients
with erosive esophagitis, grade 2 or above, PRILOSEC in a dose of
20 mg was significantly more effective than the active controls.
Complete daytime and nighttime heartburn relief occurred
significantly faster (p < 0.01) in patients treated with PRILOSEC than
in those taking placebo or histamine H2- receptor antagonists.
32
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In this and five other controlled GERD studies, significantly more
patients taking 20 mg omeprazole (84%) reported complete relief of
GERD symptoms than patients receiving placebo (12%).
Long-Term Maintenance Of Healing of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled
study, two dose regimens of PRILOSEC were studied in patients with
endoscopically confirmed healed esophagitis. Results to determine
maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
PRILOSEC
PRILOSEC
20 mg 3 days
20 mg once daily
per week
Placebo
(n = 138)
(n = 137)
(n = 131)
Percent in
endoscopic
remission at
6 months
*70
34
11
∗(p < 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 20 mg 3 consecutive days per week or
placebo.
In an international multicenter double-blind study, PRILOSEC 20 mg
daily and 10 mg daily were compared with ranitidine 150 mg twice
daily in patients with endoscopically confirmed healed esophagitis.
The table below provides the results of this study for maintenance of
healing of erosive esophagitis.
Life Table Analysis
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
10 mg once daily
150 mg twice daily
(n = 131)
(n = 133)
(n = 128)
Percent in
endoscopic
remission at
12 months
46
*77
‡58
*
(p = 0.01) PRILOSEC 20 mg once daily. versus PRILOSEC 10 mg once daily or
Ranitidine.
‡ (p = 0.03) PRILOSEC 10 mg once daily. versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for
maintenance after healing 20 mg daily of PRILOSEC was effective,
while 10 mg did not demonstrate effectiveness.
14.5 Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory
conditions, such as Zollinger-Ellison (ZE) syndrome with or without
multiple endocrine adenomas, PRILOSEC Delayed-Release Capsules
significantly inhibited gastric acid secretion and controlled associated
symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg
every other day to 360 mg per day maintained basal acid secretion
below 10 mEq/hr in patients without prior gastric surgery, and below
5 mEq/hr in patients with prior gastric surgery.
33
Reference ID: 3308075
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Initial doses were titrated to the individual patient need, and
adjustments were necessary with time in some patients [See Dosage
and Administration (2)]. PRILOSEC was well tolerated at these high
dose levels for prolonged periods (> 5 years in some patients). In
most ZE patients, serum gastrin levels were not modified by
PRILOSEC. However, in some patients serum gastrin increased to
levels greater than those present prior to initiation of omeprazole
therapy. At least 11 patients with ZE syndrome on long-term
treatment with PRILOSEC developed gastric carcinoids. These
findings are believed to be a manifestation of the underlying
condition, which is known to be associated with such tumors, rather
than the result of the administration of PRILOSEC. [See Adverse
Reactions (6)]
14.6 Pediatric GERD
Symptomatic GERD
The effectiveness of PRILOSEC for the treatment of nonerosive
GERD in pediatric patients 1 to 16 years of age is based in part on
data obtained from 125 pediatric patients in two uncontrolled Phase
III studies. [See Use in Specific Populations (8.4)]
The first study enrolled 12 pediatric patients 1 to 2 years of age with a
history of clinically diagnosed GERD. Patients were administered a
single dose of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8
weeks as an open capsule in 8.4% sodium bicarbonate solution.
Seventy-five percent (9/12) of the patients had vomiting/regurgitation
episodes decreased from baseline by at least 50%.
The second study enrolled 113 pediatric patients 2 to 16 years of age
with a history of symptoms suggestive of nonerosive GERD. Patients
were administered a single dose of omeprazole (10 mg or 20 mg,
based on body weight) for 4 weeks either as an intact capsule or as an
open capsule in applesauce. Successful response was defined as no
moderate or severe episodes of either pain-related symptoms or
vomiting/regurgitation during the last 4 days of treatment. Results
showed success rates of 60% (9/15; 10 mg omeprazole) and 59%
(58/98; 20 mg omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive
esophagitis in pediatric patients 1 to 16 years of age required doses
that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were
initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7
mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than
6% of a 24-hour study). After titration, patients remained on
treatment for 3 months. Forty-four percent of the patients were healed
on a dose of 0.7 mg/kg body weight; most of the remaining patients
were healed with 1.4 mg/kg after an additional 3 months’ treatment.
Erosive esophagitis was healed in 51 of 57 (90%) children who
completed the first course of treatment in the healing phase of the
34
Reference ID: 3308075
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study. In addition, after 3 months of treatment, 33% of the children
had no overall symptoms, 57% had mild reflux symptoms, and 40%
had less frequent regurgitation/vomiting.
Maintenance of Healing of Erosive Esophagitis
In an uncontrolled, open-label study of maintenance of healing of
erosive esophagitis in 46 pediatric patients, 54% of patients required
half the healing dose. The remaining patients increased the healing
dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire
maintenance period, or returned to half the dose before completion.
Of the 46 patients who entered the maintenance phase, 19 (41%) had
no relapse. In addition, maintenance therapy in erosive esophagitis
patients resulted in 63% of patients having no overall symptoms.
15
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods
for Dilution Antimicrobial Susceptibility Tests for Bacteria That
Grow Aerobically—Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January
2000.
16
HOW SUPPLIED/STORAGE AND HANDLING
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body. They are supplied as follows:
NDC 0186-0606-31 unit of use bottles of 30
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body. They are supplied as follows:
NDC 0186-0742-31 unit of use bottles of 30
NDC 0186-0742-82 bottles of 1000
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body. They are supplied as follows:
NDC 0186-0743-31 unit of use bottles of 30
NDC 0186-0743-68 bottles of 100
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules. PRILOSEC unit dose packets are supplied as
follows:
35
Reference ID: 3308075
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NDC 0186-0625-01 unit dose packages of 30: 2.5 mg packets
NDC 0186-0610-01 unit dose packages of 30: 10 mg packets
Storage
Store PRILOSEC Delayed-Release Capsules in a tight container
protected from light and moisture. Store between 15°C and 30°C
(59°F and 86°F).
Store PRILOSEC For Delayed-Release Oral Suspension at 25°C
(77°F); excursions permitted to 15 – 30°C (59 – 86°F). [See USP
Controlled Room Temperature].
17
PATIENT COUNSELING INFORMATION
“See FDA-Approved Medication Guide”
PRILOSEC should be taken before eating. Patients should be
informed that the PRILOSEC Delayed-Release Capsule should be
swallowed whole.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
36
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a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
Advise patients to immediately report and seek care for diarrhea that
does not improve. This may be a sign of Clostridium difficile
associated diarrhea [see Warnings and Precautions (5.3)].
Advise patients to immediately report and seek care for any
cardiovascular or neurological symptoms including palpitations,
dizziness, seizures, and tetany as these may be signs of
hypomagnesemia [see Warnings and Precautions (5.6)].
PRILOSEC is a trademark of the AstraZeneca group of companies.
Manufactured for: AstraZeneca LP, Wilmington, DE 19850
©AstraZeneca 2013
Rev.
37
Reference ID: 3308075
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MEDICATION GUIDE
PRILOSEC (pry-lo-sec)
(omeprazole)
Delayed-Release Capsules
PRILOSEC (pry-lo-sec)
(omeprazole magnesium)
For Delayed-Release Oral Suspension
Read this Medication Guide before you start taking
PRILOSEC and each time you get a refill. There may be new
information. This information does not take the place of
talking with your doctor about your medical condition or
your treatment.
What is the most important information I should
know about PRILOSEC?
PRILOSEC may help your acid-related symptoms, but
you could still have serious stomach problems. Talk
with your doctor.
PRILOSEC can cause serious side effects, including:
• Diarrhea. PRILOSEC may increase your risk of
getting severe diarrhea. This diarrhea may be caused
by an infection (Clostridium difficile) in your
intestines.
Call your doctor right away if you have watery stool,
stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily
doses of proton pump inhibitor medicines for a long
period of time (a year or longer) may have an
increased risk of fractures of the hip, wrist, or spine.
You should take PRILOSEC exactly as prescribed, at
the lowest dose possible for your treatment and for
the shortest time needed. Talk to your doctor about
your risk of bone fracture if you take PRILOSEC.
PRILOSEC can have other serious side effects. See “What
are the possible side effects of PRILOSEC?”
What is PRILOSEC?
PRILOSEC is a prescription medicine called a proton pump
inhibitor (PPI). PRILOSEC reduces the amount of acid in
your stomach.
PRILOSEC is used in adults:
• for up to 8 weeks for the healing of duodenal ulcers.
The duodenal area is the area where food passes
when it leaves the stomach.
38
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• with certain antibiotics to treat an infection caused by
bacteria called H. pylori. Sometimes H. pylori
bacteria can cause duodenal ulcers. The infection
needs to be treated to prevent the ulcers from coming
back.
• for up to 8 weeks for healing stomach ulcers
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
GERD happens when acid in your stomach backs up
into the tube (esophagus) that connects your mouth
to your stomach. This may cause a burning feeling in
your chest or throat, sour taste, or burping.
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE). If needed, your doctor may decide to prescribe
another 4 weeks of PRILOSEC.
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used for
longer than 12 months (1 year) for this purpose.
• for the long-term treatment of conditions where your
stomach makes too much acid. This includes a rare
condition called Zollinger-Ellison Syndrome.
For children 1 to 16 years of age, PRILOSEC is used:
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE)
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used longer
than 12 months (1 year) for this purpose.
It is not known if PRILOSEC is safe and effective for the
treatment of gastroesophageal reflux disease (GERD)
in children under 1 year of age.
Who should not take PRILOSEC?
Do not take PRILOSEC if you:
• are allergic to omeprazole or any of the ingredients in
PRILOSEC. See the end of this Medication Guide for a
complete list of ingredients in PRILOSEC.
• are allergic to any other Proton Pump Inhibitor (PPI)
medicine.
What should I tell my doctor before taking PRILOSEC?
39
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Before you take PRILOSEC, tell your doctor if you:
• have been told that you have low magnesium levels
in your blood
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not
known if PRILOSEC will harm your unborn baby.
• are breastfeeding or plan to breastfeed. PRILOSEC
can pass into your breast milk and may harm your
baby. You and your doctor should decide if you will
take PRILOSEC or breastfeed. You should not do both.
Talk to your doctor about the best way to feed your
baby if you breastfeed.
Tell your doctor about all of the medicines you take
including prescription and non-prescription drugs, anti
cancer drugs, vitamins and herbal supplements. PRILOSEC
may affect how other medicines work, and other medicines
may affect how PRILOSEC works.
Especially tell your doctor if you take:
• atazanavir (Reyataz)
• nelfinavir (Viracept)
• saquinavir (Fortovase)
• cilostazol (Pletal)
• ketoconazole (Nizoral)
• voriconazole (Vfend)
• an antibiotic that contains ampicillin, amoxicillin or
clarithromycin
• products that contain iron
• warfarin (Coumadin, Jantoven)
• digoxin (Lanoxin)
• tacrolimus (Prograf)
• diazepam (Valium)
• phenytoin (Dilantin)
• disulfiram (Antabuse)
• clopidogrel (Plavix)
• St. John’s Wort (Hypericum perforatum)
• rifampin (Rimactane, Rifater, Rifamate),
• erlotinib (Tarceva)
• methotrexate
Ask your doctor or pharmacist for a list of these
medicines if you are not sure.
Know the medicines that you take. Keep a list of them to
show your doctor and pharmacist when you get a new
medicine.
How should I take PRILOSEC?
•
Take PRILOSEC exactly as prescribed by your doctor.
40
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not change your dose or stop PRILOSEC without
talking to your doctor.
• Take PRILOSEC at least 1 hour before a meal.
• Swallow PRILOSEC capsules whole. Do not chew or
crush PRILOSEC Capsules.
• If you have trouble swallowing PRILOSEC Capsules,
you may take as follows:
o Place 1 tablespoon of applesauce into a clean
bowl.
o Carefully open the capsule and empty the
contents (pellets) onto the applesauce. Mix the
pellets with the applesauce.
o Swallow the applesauce and pellet mixture
right away with a glass of cool water. Do not
chew or crush the pellets. Do not store the
applesauce and pellet mixture for later use.
• If you forget to take a dose of PRILOSEC, take it as
soon as you remember. If it is almost time for your
next dose, do not take the missed dose. Take the
next dose on time. Do not take a double dose to
make up for a missed dose.
• If you take too much PRILOSEC, tell your doctor right
away.
• See the “Instructions for Use” at the end of this
Medication Guide for instructions on how to take
PRILOSEC For Delayed-Release Oral Suspension, and
how to mix and give PRILOSEC For Delayed-Release
Oral Suspension, through a nasogastric tube or
gastric tube.
What are the possible side effects of PRILOSEC?
PRILOSEC can cause serious side effects, including:
• See “What is the most important information I
should know about PRILOSEC?”
• Chronic (lasting a long time) inflammation of
the stomach lining (Atrophic Gastritis). Using
PRILOSEC for a long period of time may increase the
risk of inflammation to your stomach lining. You may
or may not have symptoms. Tell your doctor if you
have stomach pain, nausea, vomiting, or weight loss.
• Low magnesium levels in your body. This
problem can be serious. Low magnesium can happen
in some people who take a proton pump inhibitor
medicine for at least 3 months. If low magnesium
levels happen, it is usually after a year of treatment.
You may or may not have symptoms of low
magnesium.
Tell your doctor right away if you develop any of
these symptoms:
41
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
•
seizures
•
dizziness
•
abnormal or fast heart beat
•
jitteriness
•
jerking movements or shaking (tremors)
•
muscle weakness
•
spasms of the hands and feet
•
cramps or muscle aches
•
spasm of the voice box
Your doctor may check the level of magnesium in
your body before you start taking PRILOSEC or during
treatment if you will be taking PRILOSEC for a long
period of time.
The most common side effects with PRILOSEC in adults and
children include:
•
headache
•
stomach pain
•
nausea
•
diarrhea
•
vomiting
•
gas
In addition to the side effects listed above, the most
common side effects in children 1 to 16 years of age
include:
•
respiratory system events
•
fever
Other side effects:
Serious allergic reactions. Tell your doctor if you get any
of the following symptoms with PRILOSEC:
•
rash
•
face swelling
•
throat tightness
•
difficulty breathing
Your doctor may stop PRILOSEC if these symptoms
happen.
Tell your doctor if you have any side effect that bothers you
or that do not go away. These are not all the possible side
effects with PRILOSEC.
Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
42
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store PRILOSEC?
• Store PRILOSEC Delayed-Release Capsules at room
temperature between 59°F to 86°F (15°C to 30°C).
• Store PRILOSEC For Delayed-Release Oral Suspension at
room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the container of PRILOSEC Delayed-Release
Capsules closed tightly.
• Keep the container of PRILOSEC Delayed-Release
Capsules dry and away from light.
Keep PRILOSEC and all medicines out of the reach of
children.
General information about PRILOSEC
Medicines are sometimes prescribed for purposes other than
those listed in a Medication Guide. Do not use PRILOSEC for
a condition for which it was not prescribed. Do not give
PRILOSEC to other people, even if they have the same
symptoms you have. It may harm them.
This Medication Guide summarizes the most important
information about PRILOSEC. For more information, ask
your doctor. You can ask your doctor or pharmacist for
information that is written for healthcare professionals.
For more information, go to www.astrazeneca-us.com or call
1-800-236-9933.
Instructions for Use
For instructions on taking Delayed-Release Capsules, please
see “How should I take PRILOSEC?”
Take PRILOSEC For Delayed-Release Oral Suspension as
follows:
• PRILOSEC For Delayed-Release Oral Suspension
comes in packets containing 2.5 mg and 10 mg
strengths.
• You should use an oral syringe to measure the
amount of water needed to mix your dose. Ask your
pharmacist for an oral syringe.
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If you or your child are instructed to use more than
one packet for your prescribed dose, follow the
43
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
mixing instructions provided by your pharmacist or
doctor.
• Stir.
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes. If not used within
30 minutes, throw away this dose and mix a new
dose.
• If any medicine remains after drinking, add more
water, stir, and drink right away.
PRILOSEC For Delayed-Release Oral Suspension may be
given through a nasogastric tube (NG tube) or gastric tube,
as prescribed by your doctor. Follow the instructions below:
PRILOSEC For Delayed-Release Oral Suspension:
• PRILOSEC For Delayed-Release Oral Suspension
comes in packets containing 2.5 mg and 10 mg
strengths.
• Use only a catheter tipped syringe to give PRILOSEC
through a NG tube or gastric tube (French size 6 or
larger).
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• Shake the syringe right away and then leave it for 2
to 3 minutes to thicken.
• Shake the syringe and give the medicine through the
NG or gastric tube within 30 minutes.
• Refill the syringe with the same amount of water
(either 5 mL or 15 mL of water depending on your
dose).
• Shake the syringe and flush any remaining medicine
from the NG tube or gastric tube into the stomach.
What are the ingredients in PRILOSEC?
Active ingredient in PRILOSEC Delayed-Release
Capsules: omeprazole
Inactive ingredients in PRILOSEC Delayed-Release
Capsules: cellulose, disodium hydrogen phosphate,
hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate. Capsule shells: gelatin-NF, FD&C Blue
#1, FD&C Red #40, D&C Red #28, titanium dioxide,
synthetic black iron oxide, isopropanol, butyl alcohol, FD&C
Blue #2, D&C Red #7 Calcium Lake, and, in addition, the 10
mg and 40 mg capsule shells also
contain D&C Yellow #10.
44
Reference ID: 3308075
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active ingredient in PRILOSEC For Delayed-Release
Oral Suspension: omeprazole magnesium
Inactive ingredients in PRILOSEC For Delayed-Release
Oral Suspension: glyceryl monostearate, hydroxypropyl
cellulose, hypromellose, magnesium stearate, methacrylic
acid copolymer C, polysorbate, sugar spheres, talc, and
triethyl citrate.
Inactive granules in PRILOSEC For Delayed-Release
Oral Suspension: citric acid, crospovidone, dextrose,
hydroxypropyl cellulose, iron oxide and xantham gum.
This Medication Guide and Instructions for Use has been
approved by the U.S. Food and Drug Adminstration.
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Issued May 2013
PRILOSEC is a registered trademark of the AstraZeneca
group of companies.
©2012 AstraZeneca Pharmaceuticals LP. All rights reserved.
45
Reference ID: 3308075
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019810s097,022056s013lbl.pdf', 'application_number': 19810, 'submission_type': 'SUPPL ', 'submission_number': 97}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
--------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
--------------------------------------------------------------------------------------------------------
/s/
---------------------
Wiley Chambers
8/8/01 10:54:31 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19814s12lbl.pdf', 'application_number': 19814, 'submission_type': 'SUPPL ', 'submission_number': 12}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DURAGESIC safely and effectively. See full prescribing information for
DURAGESIC.
DURAGESIC (Fentanyl Transdermal System) for transdermal
administration, CII
Initial U.S. Approval: 1968
WARNING: ABUSE POTENTIAL, RESPIRATORY DEPRESSION
and DEATH, ACCIDENTAL EXPOSURE, CYTOCHROME
P450 3A4 INTERACTION, AND EXPOSURE TO HEAT
See full prescribing information for complete boxed warning.
• Contains a high concentration of fentanyl, a Schedule II controlled
substance, which is subject to misuse, abuse, addiction, and criminal
diversion. (9)
• Fatal respiratory depression could occur in patients who are not
opioid-tolerant and in patients that are opioid-tolerant even if
DURAGESIC is not misused or abused. (5)
• Accidental exposure of DURAGESIC, especially in children, can result
in a fatal overdose of fentanyl. (5)
• CYP 3A4 inhibitors can result in a fatal overdose of fentanyl from
DURAGESIC. (5)
• Avoid exposing the DURAGESIC application site and surrounding
area to direct external heat sources. Temperature dependent
increases in fentanyl release from the system may result in overdose
and death. (5)
----------------------------INDICATIONS AND USAGE---------------------------
•
DURAGESIC contains fentanyl, a full opioid agonist.
•
DURAGESIC is indicated for the management of persistent,
moderate to severe chronic pain in opioid-tolerant patients 2 years
of age and older when a continuous, around-the-clock opioid
analgesic is needed for an extended period of time. (1)
•
DURAGESIC is NOT intended for use as an as-needed
analgesic. (1)
-----------------------DOSAGE AND ADMINISTRATION----------------------
•
Individualize treatment in every case as part of a pain management
plan. (2)
•
Initial dose selection: carefully select initial dose based on the
status of each patient, consult conversion instructions. (2.1)
•
Each transdermal system is intended to be worn for 72 hours. (2.2)
•
Individually titrate to a tolerable dose that provides adequate
analgesia. (2.2)
•
Adhere to instructions concerning administration and disposal of
DURAGESIC. (2.3)
•
When DURAGESIC is no longer needed by the patient, taper the
dose as part of a pain management plan. (2.4)
•
Use with caution in the hepatic, and renally impaired patients. (2.2)
--------------------DOSAGE FORMS AND STRENGTHS---------------------
•
Transdermal system: 12 mcg/h, 25 mcg/h, 50 mcg/h, 75 mcg/h,
100 mcg/h. (3)
-------------------------------CONTRAINDICATIONS------------------------------
•
Opioid non-tolerant patients. (4)
•
Impaired pulmonary function. (4)
•
Paralytic ileus. (4)
•
Known hypersensitivity to fentanyl or any of the components of
the transdermal system. (4)
---------------------------WARNINGS AND PRECAUTIONS-------------------
•
DURAGESIC can be abused. Use caution when prescribing if
there is an increased risk of misuse, abuse, or diversion. (5.1)
•
Fatal respiratory depression can occur with DURAGESIC. Monitor
patients accordingly. Use with extreme caution in patients at risk
of respiratory depression. (5.2)
•
Accidental exposure of DURAGESIC, especially in children, can
result in a fatal overdose of fentanyl. (5.3)
•
Use DURAGESIC with extreme caution in patients susceptible to
intracranial effects of CO2 retention. (5.6)
•
DURAGESIC may have additive effects when used in conjunction
with other CNS depressants, alcohol, and drugs of abuse. (5.7)
1
•
Use of DURAGESIC with a CYP3A4 inhibitor may result in an
increase in fentanyl plasma concentrations. Monitor patients
accordingly and adjust dosage if necessary. (5.8)
•
DURAGESIC may produce bradycardia. Administer with caution
to patients with bradyarrhythmias. (5.11)
•
Use DURAGESIC with caution in patients with pancreatic/biliary
disease. (5.14)
------------------------------ADVERSE REACTIONS-----------------------------
The most common adverse reactions (≥5%) in a double-blind, randomized,
placebo-controlled clinical trial in patients with severe pain were nausea,
vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis,
fatigue, feeling cold, and anorexia. Other common adverse reactions (≥5%)
reported in clinical trials in patients with chronic malignant or nonmalignant
pain were headache and diarrhea. (6.0)
To report SUSPECTED ADVERSE REACTIONS, call 1-800-526-7736 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS---------------------------
•
Monitor patients receiving DURAGESIC and any CYP3A4
inhibitor for an extended period of time and adjust dosage, if
necessary. (7.1)
•
Use CNS Depressants with caution and in reduced dosage in
patients who are receiving DURAGESIC. (7.2)
•
Avoid DURAGESIC in patients taking a monoamine oxidase
(MAO) inhibitor or within 14 days of stopping such treatment.
(7.3)
-----------------------USE IN SPECIFIC POPULATIONS----------------------
•
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
•
Nursing Mothers: Breast-feeding is not advised in mothers treated
with DURAGESIC. (8.3)
•
Pediatric Use: Safety and efficacy in pediatric patients below the
age of 2 years have not been established. To guard against
accidental ingestion by children, use caution when choosing the
application site for DURAGESIC. (8.4)
•
Geriatric Use: Administer DURAGESIC with caution, and in
reduced dosages in elderly patients. (8.5)
•
Hepatic or Renal Impairment: Administer DURAGESIC with
caution. Monitor for signs of fentanyl toxicity and reduce dosage,
if necessary. (8.6, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 09/2013
Reference ID: 3380191
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ABUSE POTENTIAL, RESPIRATORY DEPRESSION
AND DEATH, ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4
INTERACTION, AND EXPOSURE TO HEAT
Boxed Warning
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Proper Patient Selection
2.2
Dosing
2.3
Titration and Maintenance of Therapy
2.4
Administration of DURAGESIC
2.5
Disposal Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Abuse Potential
5.2
Respiratory Depression and Death
5.3
Accidental Exposure
5.4
Elderly, Cachectic, and Debilitated Patients
5.5
Chronic Pulmonary Disease
5.6
Head Injuries and Increased Intracranial Pressure
5.7
Interactions with Other CNS Depressants,
Alcohol, and Drugs of Abuse
5.8
Interactions with CYP3A4 Inhibitors
5.9
Application of External Heat
5.10 Patients with Fever
5.11 Cardiac Disease
5.12 Hepatic Impairment
5.13 Renal Impairment
5.14 Use in Pancreatic/Biliary Tract Disease
5.15 Avoidance of Withdrawal
5.16 Driving and Operating Machinery
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Post-Marketing Experience
7
DRUG INTERACTIONS
7.1
Agents Affecting Cytochrome P450 3A4
Isoenzyme System
7.2
Central Nervous System Depressants
7.3
MAO Inhibitors
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
8.8
Neonatal Opioid Withdrawal Syndrome
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10 OVERDOSAGE
10.1 Clinical Presentation
10.2 Treatment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of
Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
[*Sections or subsections omitted from the full prescribing information
are not listed]
2
Reference ID: 3380191
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ABUSE POTENTIAL , RESPIRATORY DEPRESSION and DEATH,
ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4 INTERACTION, AND
EXPOSURE TO HEAT
Abuse Potential
DURAGESIC contains fentanyl, an opioid agonist and a Schedule II controlled substance
with an abuse liability similar to other opioid analgesics. DURAGESIC can be abused in a
manner similar to other opioid agonists, legal or illicit. Persons at increased risk for opioid
abuse include those with a personal or family history of substance abuse (including drug or
alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for
their clinical risks for opioid abuse or addiction prior to prescribing DURAGESIC and
then routinely monitor all patients for signs of misuse, abuse and addiction during
treatment [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9)].
Respiratory Depression and Death
Respiratory depression and death may occur with use of DURAGESIC, even when
DURAGESIC has been used as recommended and not misused or abused. Proper dosing
and titration are essential and DURAGESIC should only be prescribed by healthcare
professionals who are knowledgeable in the use of potent opioids for the management of
chronic pain. DURAGESIC is contraindicated for use in conditions in which the risk of
life-threatening respiratory depression is significantly increased, including use as an as-
needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain.
Monitor for respiratory depression, especially during the first two applications following
initiation of dosing, or following an increase in dosage [see Contraindications (4) and
Warnings and Precautions (5.2)].
Accidental Exposure
Death and other serious medical problems have occurred when children and adults were
accidentally exposed to DURAGESIC. Advise patients about strict adherence to the
recommended handling and disposal instructions in order to prevent accidental exposure
[see Dosage and Administration (2.3) (2.4) and Warnings and Precautions (5.3)].
Cytochrome P450 3A4 Interaction
The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors may result
in an increase in fentanyl plasma concentrations, which could increase or prolong adverse
drug effects and may cause potentially fatal respiratory depression. Monitor patients
receiving DURAGESIC and any CYP3A4 inhibitor [see Warnings and Precautions (5.8),
Reference ID: 3380191
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and Clinical Pharmacology (12.3)].
Exposure To Heat
The DURAGESIC application site and surrounding area must not be exposed to direct
external heat sources, such as heating pads or electric blankets, heat or tanning lamps,
sunbathing, hot baths, saunas, hot tubs, and heated water beds. Exposure to heat may
increase fentanyl absorption and there have been reports of overdose and death as a result
of exposure to heat (5.9). Patients wearing DURAGESIC systems who develop fever or
increased core body temperature due to strenuous exertion are also at risk for increased
fentanyl exposure and may require an adjustment in the dose of DURAGESIC to avoid
overdose and death (5.10).
1
INDICATIONS AND USAGE
DURAGESIC is a transdermal formulation of fentanyl indicated for the management of
persistent, moderate to severe chronic pain in opioid-tolerant patients 2 years of age and older
when a continuous, around-the-clock opioid analgesic is required for an extended period of time,
and the patient cannot be managed by other means such as non-steroidal analgesics, opioid
combination products, or immediate-release opioids.
Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or
at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an
equianalgesic dose of another opioid for a week or longer.
2
DOSAGE AND ADMINISTRATION
2.1
Proper Patient Selection
Abuse Potential
Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribing
DURAGESIC [see Warnings and Precautions (5.1)].
Opioid Tolerance
Opioid tolerance to an opioid of comparable potency must be established before prescribing
DURAGESIC [see Warnings and Precautions (5.2)].
Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or
at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an
equianalgesic dose of another opioid for a week or longer.
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Dosing
Conversion to DURAGESIC in Opioid-Tolerant Patients
The recommended starting dose when converting from other opioids to DURAGESIC is
intended to minimize the potential for overdosing patients with the first dose. Monitor patients
closely for respiratory depression, especially within the first 24-72 hours of initiating therapy
with DURAGESIC [see Warnings and Precautions (5.2)].
In selecting an initial DURAGESIC dose, take the following factors into account:
1. the daily dose, potency, and characteristics of the opioid the patient has been taking
previously (e.g., whether it is a pure agonist or mixed agonist-antagonist);
2. the reliability of the relative potency estimates used to calculate the DURAGESIC dose
needed (potency estimates may vary with the route of administration);
3. the degree of opioid tolerance;
4. the general condition and medical status of the patient.
To convert adult and pediatric patients from oral or parenteral opioids to DURAGESIC, use
Table 1. Do not use Table 1 to convert from DURAGESIC to other therapies because this
conversion to DURAGESIC is conservative and will overestimate the dose of the new agent.
TABLE 11: DOSE CONVERSION GUIDELINES
Current Analgesic
Daily Dosage (mg/day)
Oral morphine
60-134
135-224
225-314
315-404
Intramuscular or
10-22
23-37
38-52
53-67
Intravenous morphine
Oral oxycodone
30-67
67.5-112
112.5-157
157.5-202
Oral codeine
150-447
Oral hydromorphone
8-17
17.1-28
28.1-39
39.1-51
Intravenous
1.5-3.4
3.5-5.6
5.7-7.9
8-10
hydromorphone
Intramuscular meperidine
75-165
166-278
279-390
391-503
Oral methadone
20-44
45-74
75-104
105-134
⇓
⇓
⇓
⇓
Recommended
25 mcg/hour
50 mcg/hour
75 mcg/hour
100 mcg/hour
DURAGESIC Dose
Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion
methodology outlined above with Table 2.
1 Table 1 should not be used to convert from DURAGESIC to other therapies because this conversion to
DURAGESIC is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the
dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration
(2.3)].
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use
the following methodology:
1. Calculate the previous 24-hour analgesic requirement.
2. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.
Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for
conversion to each DURAGESIC dose. Use this table to find the calculated 24-hour morphine
dose and the corresponding DURAGESIC dose. Initiate DURAGESIC treatment using the
recommended dose and titrate patients upwards (no more frequently than 3 days after the initial
dose and every 6 days thereafter) until analgesic efficacy is attained.
3. Do not use Table 2 to convert from DURAGESIC to other therapies because this
conversion to DURAGESIC is conservative and will overestimate the dose of the new agent.
TABLE 21:
RECOMMENDED INITIAL DURAGESIC DOSE BASED UPON DAILY ORAL
MORPHINE DOSE
Oral 24-hour
DURAGESIC
Morphine
Dose
(mg/day)
(mcg/hour)
60-134
25
135-224
50
225-314
75
315-404
100
405-494
125
495-584
150
585-674
175
675-764
200
765-854
225
855-944
250
945-1034
275
1035-1124
300
NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to
DURAGESIC.
1 Table 2 should not be used to convert from DURAGESIC to other therapies because this conversion to
DURAGESIC is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the
dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration
(2.3)].
For delivery rates in excess of 100 mcg/hour, multiple systems may be used.
Hepatic Impairment
Avoid the use of DURAGESIC in patients with severe hepatic impairment. In patients with mild
to moderate hepatic impairment, start with one half of the usual dosage of DURAGESIC.
Closely monitor for signs of sedation and respiratory depression, including at each dosage
increase [see Warnings and Precautions (5.12), Use in Specific Populations (8.6) and Clinical
Pharmacology (12.3)].
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal Impairment
Avoid the use of DURAGESIC in patients with severe renal impairment. In patients with mild to
moderate renal impairment, start with one half of the usual dosage of DURAGESIC. Closely
monitor for signs of sedation and respiratory depression, including at each dosage increase [see
Warnings and Precautions (5.13), Use in Specific Populations (8.7) and Clinical Pharmacology
(12.3)].
2.3
Titration and Maintenance of Therapy
Once therapy is initiated, assess pain intensity and opioid adverse reactions frequently, especially
respiratory depression [see Warnings and Precautions (5.2)]. Routinely monitor all patients for
signs of misuse, abuse and addiction [see Warnings and Precautions (5.1)].
The initial DURAGESIC dose may be increased after 3 days based on the daily dose of
supplemental opioid analgesics required by the patient on the second or third day of the initial
application.
It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical
Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-
day applications before any further increase in dosage is made.
Base dosage increments on the daily dosage of supplementary opioids, using the ratio of
45 mg/24 hours of oral morphine to a 12 mcg/hour increase in DURAGESIC dose.
The majority of patients are adequately maintained with DURAGESIC administered every
72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may
require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control
cannot be achieved using a 72-hour regimen. An increase in the DURAGESIC dose should be
evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen.
Dosing intervals less than every 72 hours were not studied in children and adolescents and are
not recommended.
Discontinuation of DURAGESIC
To convert patients to another opioid, remove DURAGESIC and titrate the dose of the new
analgesic based upon the patient’s report of pain until adequate analgesia has been attained.
Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl
concentrations. Withdrawal symptoms are possible in some patients after conversion or dose
adjustment [see Warnings and Precautions (5.15)].
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not use Tables 1 and 2 to convert from DURAGESIC to other therapies to avoid
overestimating the dose of the new agent potentially resulting in overdose of the new analgesic
and death.
When discontinuing DURAGESIC and not converting to another opioid, use a gradual
downward titration, such as halving the dose every 6 days, in order to reduce the possibility of
withdrawal symptoms [see Warnings and Precautions (5.15)]. It is not known at what dose level
DURAGESIC may be discontinued without producing the signs and symptoms of opioid
withdrawal.
2.4
Administration of DURAGESIC
DURAGESIC patches are for transdermal use, only.
Proper handling of DURAGESIC is advised in order to prevent adverse reactions,
including death, associated with accidental secondary exposure to DURAGESIC [see
Warnings and Precautions (5.3)].
Application and Handling Instructions
• Patients should apply DURAGESIC to intact, non-irritated, and non-irradiated skin on a flat
surface such as the chest, back, flank, or upper arm. In young children and persons with
cognitive impairment, adhesion should be monitored and the upper back is the preferred
location to minimize the potential of inappropriate patch removal. Hair at the application site
may be clipped (not shaved) prior to system application. If the site of DURAGESIC
application must be cleansed prior to application of the patch, do so with clear water. Do not
use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its
characteristics. Allow the skin to dry completely prior to patch application.
• Patients should apply DURAGESIC immediately upon removal from the sealed package.
The patch must not be altered (e.g., cut) in any way prior to application. DURAGESIC
should not be used if the pouch seal is broken or if the patch is cut or damaged.
• The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds,
making sure the contact is complete, especially around the edges.
• Each DURAGESIC patch may be worn continuously for 72 hours. The next patch is applied
to a different skin site after removal of the previous transdermal system.
• If problems with adhesion of the DURAGESIC patch occur, the edges of the patch may be
taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a
transparent adhesive film dressing.
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the
toilet. A new patch may be applied to a different skin site.
• Patients (or caregivers who apply DURAGESIC) should wash their hands immediately with
soap and water after applying DURAGESIC.
• Contact with unwashed or unclothed application sites can result in secondary exposure to
DURAGESIC and should be avoided. Examples of accidental exposure include transfer of a
DURAGESIC patch from an adult’s body to a child while hugging, sharing the same bed as
the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s
skin to the medication in the patch while applying or removing the patch.
• Instruct patients, family members, and caregivers to keep patches in a secure location out of
the reach of children and of others for whom DURAGESIC was not prescribed.
Avoidance of Heat
Instruct patients to avoid exposing the DURAGESIC application site and surrounding area to
direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps,
sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see
Warnings and Precautions (5.9)].
2.5
Disposal Instructions
Proper disposal of DURAGESIC is advised in order to prevent adverse reactions, including
death, associated with accidental secondary exposure to DURAGESIC [see Warnings and
Precautions (5.3)].
Patients should dispose of used patches by folding the adhesive side of the patch to itself, then
flush the patch down the toilet immediately upon removal.
Patients should dispose of any patches remaining from a prescription as soon as they are no
longer needed. Unused patches should be removed from their pouches, fold so that the adhesive
side of the patch adheres to itself, and flush down the toilet.
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DOSAGE FORMS AND STRENGTHS
DURAGESIC is available as:
• DURAGESIC 12 mcg/hour* Transdermal System (system size 5.25 cm2).
• DURAGESIC 25 mcg/hour Transdermal System (system size 10.5 cm2).
• DURAGESIC 50 mcg/hour Transdermal System (system size 21 cm2).
• DURAGESIC 75 mcg/hour Transdermal System (system size 31.5 cm2).
• DURAGESIC 100 mcg/hour Transdermal System (system size 42 cm2).
*This lowest dosage is designated as 12 mcg/hour (however, the actual dosage is 12.5 mcg/hour) to distinguish it
from a 125 mcg/h dosage that could be prescribed by multiple patches.
4 CONTRAINDICATIONS
DURAGESIC is contraindicated in the following patients and situations due to the risk of fatal
respiratory depression:
• in patients who are not opioid-tolerant [see Warnings and Precautions (5.2)].
• in the management of acute or intermittent pain, or in patients who require opioid
analgesia for a short period of time [see Warnings and Precautions (5.2)].
• in the management of post-operative pain, including use after out-patient or day
surgeries, (e.g., tonsillectomies) [see Warnings and Precautions (5.2)].
• in the management of mild pain [see Warnings and Precautions (5.2)].
• in patients with significant respiratory compromise, especially if adequate monitoring
and resuscitative equipment are not readily available [see Warnings and Precautions
(5.2)].
• in patients who have acute or severe bronchial asthma [see Warnings and Precautions
(5.2)].
DURAGESIC is also contraindicated:
• in patients who have or are suspected of having paralytic ileus
• in patients with known hypersensitivity to fentanyl or any components of the
transdermal system. Severe hypersensitivity reactions, including anaphylaxis have been
observed with DURAGESIC [see Adverse Reactions (6.2].
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS AND PRECAUTIONS
5.1
Abuse Potential
DURAGESIC contains fentanyl, an opioid agonist and a Schedule II controlled substance with
an abuse liability similar to other opioid analgesics. Schedule II opioid substances which include
hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest
potential for abuse and risk of fatal overdose due to respiratory depression. DURAGESIC can be
abused in a manner similar to other opioid agonists, legal or illicit. These risks should be
considered when administering, prescribing, or dispensing DURAGESIC in situations where the
healthcare professional is concerned about increased risk of misuse, abuse, or diversion [see
Drug Abuse and Dependence (9)].
Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed
opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction
since use of opioid analgesic products carries the risk of addiction even under appropriate
medical use. Persons at increased risk for opioid abuse include those with a personal or family
history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g.,
major depression). Patients at increased risk may still be appropriately treated with modified-
release opioid formulations; however these patients will require intensive monitoring for signs of
misuse, abuse, or addiction. Concerns about abuse, addiction, and diversion should not prevent
the proper management of pain.
Contact local state professional licensing board or state controlled substances authority for
information on how to prevent and detect abuse or diversion of this product.
5.2
Respiratory Depression and Death
Respiratory depression is the chief hazard of DURAGESIC. Respiratory depression, if not
immediately recognized and treated, may lead to respiratory arrest and death.
DURAGESIC has a narrow indication and should be prescribed only by healthcare professionals
who are knowledgeable in the administration of potent opioids and management of chronic pain
[see Indications and Usage (1)]. DURAGESIC is contraindicated for use in conditions in which
the risk of life-threatening respiratory depression is significantly increased, including use as an
as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain [see
Contraindications (4)]. Proper dosing and titration of DURAGESIC are essential [see Dosage
and Administration (2.3)]. Overestimating the DURAGESIC dose when converting patients from
another opioid medication, can result in fatal overdose with the first dose. However, respiratory
depression has also been reported with use of DURAGESIC in patients who are opioid-tolerant,
even when DURAGESIC has been used as recommended and not misused or abused.
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean half-life of fentanyl when delivered by DURAGESIC is approximately 20-27 hours.
Serum fentanyl concentrations continue to rise for the first two system applications. In addition,
significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after
the patch is removed [see Clinical Pharmacology (12.3)].
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased
rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated
by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory
depression can exacerbate the sedating effects of opioids.
While serious, life-threatening or fatal respiratory depression can occur at any time during the
use of DURAGESIC, the potential for serious, life threatening, or fatal respiratory depression is
greatest during the first two applications following initiation of dosing, or following an increase
in dosage. Closely monitor patients for respiratory depression when initiating therapy with
DURAGESIC, especially within the initial 24-72 hours when serum concentrations from the
initial patch will peak, and following increases in dosage. Because significant amounts of
fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed,
respiratory depression may persist beyond the removal of DURAGESIC. Monitor patients for
respiratory depression after patch removal to ensure that the patient’s respiration has stabilized
for at least 24 to 72 hours or longer as clinical symptoms dictate.
Management of respiratory depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient’s clinical status [see Overdose (10.2)].
5.3
Accidental Exposure
A considerable amount of active fentanyl remains in DURAGESIC even after use as directed.
Death and other serious medical problems have occurred when children and adults were
accidentally exposed to DURAGESIC. Accidental or deliberate application or ingestion by a
child or adolescent will cause respiratory depression that could result in death. Placing
DURAGESIC in the mouth, chewing it, swallowing it, or using it in ways other than indicated
may cause choking or overdose that could result in death.
Advise patients about strict adherence to the recommended handling and disposal instructions in
order to prevent accidental exposure to DURAGESIC (see Dosage and Administration (2.4)
(2.5)].
5.4
Elderly, Cachectic, and Debilitated Patients
Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they
may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance.
Therefore, monitor these patients closely, particularly when initiating therapy with DURAGESIC
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and when given in conjunction with other drugs that depress respiration [see Warnings and
Precautions (5.2) and Use in Specific Populations (8.5)].
5.5
Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and
patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-
existing respiratory depression for respiratory depression, particularly when initiating therapy
with DURAGESIC, as in these patients, even usual therapeutic doses of DURAGESIC may
decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider
the use of alternative non-opioid analgesics in these patients if possible.
5.6
Head Injuries and Increased Intracranial Pressure
Avoid use of DURAGESIC in patients who may be particularly susceptible to the intracranial
effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired
consciousness, or coma [see Warnings and Precautions (5.2)]. In addition, opioids may obscure
the clinical course of patients with head injury. Monitor patients with brain tumors who may be
susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory
depression, particularly when initiating therapy with DURAGESIC, as DURAGESIC may
reduce respiratory drive and CO2 retention can further increase intracranial pressure.
5.7
Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse
The concomitant use of DURAGESIC with other central nervous system depressants, including,
but not limited to, other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines),
general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory
depression, hypotension, and profound sedation or coma. Monitor patients prescribed
concomitant CNS active drugs for signs of sedation and respiratory depression, particularly when
initiating therapy with DURAGESIC, and reduce the dose of one or both agents [see Warnings
and Precautions (5.2)].
5.8
Interactions with CYP3A4 Inhibitors
The concomitant use of DURAGESIC with a CYP3A4 inhibitors (such as ritonavir,
ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) may
result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse
drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients
receiving DURAGESIC and any CYP3A4 inhibitor for signs of sedation and respiratory
depression for an extended period of time, and make dosage adjustments if warranted [see
Warnings and Precautions (5.2), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Reference ID: 3380191
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9
Application of External Heat
Exposure to heat may increase fentanyl absorption and there have been reports of overdose and
death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult
subjects has shown that the application of heat over the DURAGESIC system increased fentanyl
exposure [see Clinical Pharmacology (12.3)].
Warn patients to avoid exposing the DURAGESIC application site and surrounding area to direct
external heat sources [see Dosage and Administration (2.4)].
5.10 Patients with Fever
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase
by approximately one-third for patients with a body temperature of 40°C (104°F) due to
temperature-dependent increases in fentanyl released from the system and increased skin
permeability. Monitor patients wearing DURAGESIC systems who develop fever closely for
opioid side effects and reduce the DURAGESIC dose if necessary. Warn patients to avoid
strenuous exertion that leads to increased core body temperature while wearing DURAGESIC to
avoid the risk of potential overdose and death.
5.11 Cardiac Disease
DURAGESIC may produce bradycardia. Monitor patients with bradyarrhythmias closely for
changes in heart rate, particularly when initiating therapy with DURAGESIC.
5.12 Hepatic Impairment
A clinical pharmacology study with DURAGESIC in patients with cirrhosis has shown that
systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl
when administered as DURAGESIC and hepatic metabolism of fentanyl, avoid use of
DURAGESIC in patients with severe hepatic impairment. Insufficient information exists to make
precise dosing recommendations regarding the use of DURAGESIC in patients with impaired
hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment
on too high of a dose, start with one half of the usual dosage of DURAGESIC. Closely monitor
for signs of sedation and respiratory depression, including at each dosage increase. [see Dosing
and Administration (2.2),Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
5.13 Renal Impairment
A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney
transplantation has shown that patients with high blood urea nitrogen level had low fentanyl
clearance. Because of the long half-life of fentanyl when administered as DURAGESIC, avoid
the use of DURAGESIC in patients with severe renal impairment. Insufficient information exists
to make precise dosing recommendations regarding the use of DURAGESIC in patients with
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
impaired renal function. Therefore, to avoid starting patients with mild to moderate renal
impairment on too high of a dose, start with one half of the usual dosage of DURAGESIC.
Closely monitor for signs of sedation and respiratory depression, including at each dosage
increase [see Dosing and Administration (2.2), Use in Specific Populations (8.7) and Clinical
Pharmacology (12.3)].
5.14 Use in Pancreatic/Biliary Tract Disease
DURAGESIC may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract
disease, including acute pancreatitis for worsened symptoms. DURAGESIC may cause increases
in the serum amylase concentration.
5.15 Avoidance of Withdrawal
Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are
possible in some patients after conversion to another opioid or when decreasing or discontinuing
DURAGESIC. Gradual reduction of the dose of DURAGESIC is recommended [see Dosage and
Administration (2.3) and Drug Abuse and Dependence (9)].
5.16 Driving and Operating Machinery
Strong opioid analgesics impair the mental or physical abilities required for the performance of
potentially dangerous tasks, such as driving a car or operating machinery. Warn patients not to
drive or operate dangerous machinery unless they are tolerant to the effects of the DURAGESIC.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Abuse Potential [see Warnings and Precautions (5.1)]
• Respiratory Depression [see Warnings and Precautions (5.2)]
• Accidental Exposure [see Warnings and Precautions (5.3)]
• Elderly, Cachetic, and Debilitated Patients [see Warnings and Precautions (5.4)]
• Chronic Pulmonary Disease [see Warnings and Precautions (5.5)]
• Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.6)]
• Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse [see Warnings
and Precautions (5.7)]
• Interactions with CYP3A4 Inhibitors [see Warnings and Precautions (5.8)]
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Application of External Heat [see Warnings and Precautions (5.9)]
• Patients with Fever [see Warnings and Precautions (5.10)]
• Cardiac Disease [see Warnings and Precautions (5.11)]
• Hepatic Impairment [see Warnings and Precautions (5.12)]
• Renal Impairment [see Warnings and Precautions (5.13)]
• Use in Pancreatic/Biliary Tract Disease [see Warnings and Precautions (5.14)]
• Avoidance of Withdrawal [see Warnings and Precautions (5.15)]
• Driving and Operating Machinery [see Warnings and Precautions (5.16)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
6.1
Clinical Trial Experience
The safety of DURAGESIC was evaluated in 216 patients who took at least one dose of
DURAGESIC in a multicenter, double-blind, randomized, placebo-controlled clinical trial of
DURAGESIC. This trial examined patients over 40 years of age with severe pain induced by
osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.
The most common adverse reactions (≥5%) in a double-blind, randomized, placebo-controlled
clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness,
insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse
reactions (≥5%) reported in clinical trials in patients with chronic malignant or nonmalignant
pain were headache and diarrhea. Adverse reactions reported for ≥1% of DURAGESIC-treated
patients and with an incidence greater than placebo-treated patients are shown in Table 3.
The most common adverse reactions that were associated with discontinuation in patients with
pain (causing discontinuation in ≥1% of patients) were depression, dizziness, somnolence,
headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3.
Adverse Reactions Reported by ≥1% of DURAGESIC-treated Patients and
With an Incidence Greater Than Placebo-treated Patients in 1 Double-
Blind, Placebo-Controlled Clinical Trial of DURAGESIC
DURAGESIC
Placebo
System/Organ Class
%
%
Adverse Reaction
(N=216)
(N=200)
Cardiac disorders
Palpitations
4
1
Ear and labyrinth disorders
Vertigo
2
1
Gastrointestinal disorders
Nausea
41
17
Vomiting
26
3
Constipation
9
1
Abdominal pain upper
3
2
Dry mouth
2
0
General disorders and administration
site conditions
Fatigue
6
3
Feeling cold
6
2
Malaise
4
1
Asthenia
2
0
Edema peripheral
1
1
Metabolism and nutrition disorders
Anorexia
5
0
Musculoskeletal and connective tissue
disorders
Muscle spasms
4
2
Nervous system disorders
Somnolence
19
3
Dizziness
10
4
Psychiatric disorders
Insomnia
10
7
Depression
1
0
Skin and subcutaneous tissue disorders
Hyperhidrosis
6
1
Pruritus
3
2
Rash
2
1
Adverse reactions not reported in Table 1 that were reported by ≥1% of DURAGESIC-treated
adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of
DURAGESIC used for the treatment of chronic malignant or nonmalignant pain are shown in
Table 4.
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Table 4.
Adverse Reactions Reported by ≥1% of DURAGESIC-treated Patients in
11 Clinical Trials of DURAGESIC
DURAGESIC
System/Organ Class
%
Adverse Reaction
(N=1854)
Gastrointestinal disorders
Diarrhea
10
Abdominal pain
3
Immune system disorders
Hypersensitivity
1
Nervous system disorders
Headache
12
Tremor
3
Paresthesia
2
Psychiatric disorders
Anxiety
3
Confusional state
2
Hallucination
1
Renal and urinary disorders
Urinary retention
1
Skin and subcutaneous tissue disorders
Erythema
1
The following adverse reactions occurred in adult and pediatric patients with an overall
frequency of <1% and are listed in descending frequency within each System/Organ Class:
Cardiac disorders: cyanosis
Eye disorders: miosis
Gastrointestinal disorders: subileus
General disorders and administration site conditions: application site reaction, influenza-like
illness, application site hypersensitivity, drug withdrawal syndrome, application site
dermatitis
Musculoskeletal and connective tissue disorders: muscle twitching
Nervous system disorders: hypoesthesia
Psychiatric disorders: disorientation, euphoric mood
Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction
Respiratory, thoracic and mediastinal disorders: respiratory depression
Skin and subcutaneous tissue disorders: eczema, dermatitis allergic, dermatitis contact
Pediatrics
The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients
with chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥1% of
DURAGESIC-treated pediatric patients are shown in Table 5.
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Table 5.
Adverse Reactions Reported by ≥1% of DURAGESIC-treated Pediatric
Patients in 3 Clinical Trials of DURAGESIC
DURAGESIC
System/Organ Class
%
Adverse Reaction
(N=289)
Gastrointestinal disorders
Vomiting
34
Nausea
24
Constipation
13
Diarrhea
13
Abdominal pain
9
Abdominal pain upper
4
Dry mouth
2
General disorders and administration site conditions
Edema peripheral
5
Fatigue
2
Application site reaction
1
Asthenia
1
Immune system disorders
Hypersensitivity
3
Metabolism and nutrition disorders
Anorexia
4
Musculoskeletal and connective tissue disorders
Muscle spasms
2
Nervous system disorders
Headache
16
Somnolence
5
Dizziness
2
Tremor
2
Hypoesthesia
1
Psychiatric disorders
Insomnia
6
Anxiety
4
Depression
2
Hallucination
2
Renal and urinary disorders
Urinary retention
3
Respiratory, thoracic and mediastinal disorders
Respiratory depression
1
Skin and subcutaneous tissue disorders
Pruritus
13
Rash
6
Hyperhidrosis
3
Erythema
3
6.2
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of DURAGESIC.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency.
Cardiac Disorders: Tachycardia, Bradycardia
Eye Disorders: Vision blurred
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Gastrointestinal Disorders: Ileus, Dyspepsia
General Disorders and Administration Site Conditions: Feeling of body temperature change
Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Investigations: Weight decreased
Nervous System Disorders: Convulsions (including Clonic convulsions and Grand mal
convulsion), Amnesia
Psychiatric Disorders: Agitation
Respiratory, Thoracic, and Mediastinal Disorders: Respiratory distress, Apnea, Bradypnea,
Hypoventilation, Dyspnea
Vascular Disorders: Hypotension, Hypertension
7
DRUG INTERACTIONS
7.1
Agents Affecting Cytochrome P450 3A4 Isoenzyme System
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system
(CYP3A4). Coadministration with agents that induce CYP3A4 activity may reduce the efficacy
of DURAGESIC. The concomitant use of DURAGESIC with a CYP3A4 inhibitor (such as
ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfanivir, nefazadone,
amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir,
verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which
could increase or prolong adverse drug effects and may cause fatal respiratory depression.
Closely monitor patients receiving DURAGESIC and any CYP3A4 inhibitor and reduce the
dosage of DURAGESIC if warranted [see Clinical Pharmacology (12.3)].
7.2
Central Nervous System Depressants
The concomitant use of DURAGESIC with other central nervous system depressants, including
but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines),
general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory
depression, hypotension, and profound sedation, or potentially result in coma or death. Monitor
patients closely when central nervous system depressants are used concomitantly with
DURAGESIC and reduce the dose of one or both agents.
7.3
MAO Inhibitors
Avoid use of DURAGESIC in the patient who would require the concomitant administration of a
monoamine oxidase (MAO) inhibitor, or within 14 days of stopping such treatment because
severe and unpredictable potentiation by MAO inhibitors has been reported with opioid
analgesics.
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8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic Effects
Pregnancy C: There are no adequate and well-controlled studies in pregnant women.
DURAGESIC should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse,
and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or
500 µg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted
microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is
approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2
basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred
female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight
increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of
teratogenicity noted.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg)
via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease
in the body weight of the live fetuses at the high dose, which may be attributed to maternal
toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse
effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily
human dose administered by a 100 mcg/hr patch on a mg/m2 basis).
Nonteratogenic Effects
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient
respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence
syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were
no more frequent than expected in most studies of infants born to women treated acutely during
labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been
observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat
model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via
intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment
(0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased
survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated
alterations in some physical landmarks of development (delayed incisor eruption and eye
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opening) and transient behavioral development (decreased locomotor activity at day 28 which
recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human
dose administered by a 100 mcg/hr patch on a mg/m2 basis.
8.2
Labor and Delivery
Fentanyl readily passes across the placenta to the fetus; therefore, DURAGESIC is not
recommended for analgesia during labor and delivery.
8.3
Nursing Mothers
Fentanyl is excreted in human milk; therefore, DURAGESIC is not recommended for use in
nursing women because of the possibility of effects in their infants.
8.4
Pediatric Use
The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients
with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher
were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral
morphine or an equianalgesic dose of another opioid. Initiation of DURAGESIC therapy in
pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of
another opioid has not been evaluated in controlled clinical trials.
The safety and effectiveness of DURAGESIC in children under 2 years of age have not been
established.
To guard against excessive exposure to DURAGESIC by young children, advise caregivers to
strictly adhere to recommended DURAGESIC application and disposal instructions [see Dosage
and Administration (2.4)(2.5) and Warnings and Precautions (5.3)].
8.5
Geriatric Use
Clinical studies of DURAGESIC did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced
clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the
active substance than younger patients. A study conducted with the DURAGESIC patch in
elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from
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young adult subjects, although peak serum concentrations tended to be lower and mean half-life
values were prolonged to approximately 34 hours [see Clinical Pharmacology (12.3)].
Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly
when initiating therapy with DURAGESIC and when given in conjunction with other drugs that
depress respiration [see Warnings and Precautions (5.2)(5.4)].
8.6
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of DURAGESIC has not been fully
evaluated. A clinical pharmacology study with DURAGESIC in patients with cirrhosis has
shown that systemic fentanyl exposure increased in these patients. Because there is in-vitro and
in-vivo evidence of extensive hepatic contribution to the elimination of DURAGESIC, hepatic
impairment would be expected to have significant effects on the pharmacokinetics of
DURAGESIC. Avoid use of DURAGESIC in patients with severe hepatic impairment [see
Dosing and Administration (2.2), Warnings and Precautions (5.12) and Clinical Pharmacology
12.3)].
8.7
Renal Impairment
The effect of renal impairment on the pharmacokinetics of DURAGESIC has not been fully
evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing
kidney transplantation has shown that patients with high blood urea nitrogen level had low
fentanyl clearance. Because there is in-vivo evidence of renal contribution to the elimination of
DURAGESIC, renal impairment would be expected to have significant effects on the
pharmacokinetics of DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal
impairment [see Dosing and Administration (2.2), Warnings and Precautions (5.13) and Clinical
Pharmacology (12.3)].
8.8
Neonatal Opioid Withdrawal Syndrome
Chronic maternal use of fentanyl can affect the neonate with subsequent withdrawal signs.
Neonatal withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern,
high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration and
severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the
dosage of last maternal use, and rate of elimination of the drug by the newborn. Neonatal opioid
withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and
should be treated according to protocols developed by neonatology experts.
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9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
DURAGESIC contains fentanyl, a potent Schedule II opioid agonist. Schedule II opioid
substances,
which
include
hydromorphone,
methadone,
morphine,
oxycodone,
and
oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory
depression. DURAGESIC can be abused and is subject to criminal diversion [see Warnings and
Precautions (5.1)].
9.2
Abuse
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a
multidisciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions
and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug
abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physicians should be aware that addiction may be accompanied by concurrent tolerance and
symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true
addiction and is characterized by misuse for non-medical purposes, often in combination with
other psychoactive substances. Since DURAGESIC may be diverted for non-medical use, careful
recordkeeping of prescribing information, including quantity, frequency, and renewal requests is
strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
drugs.
9.3
Dependence
Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a
diminution of one or more of the drug’s effects over time. Tolerance may occur to both the
desired and undesired effects of drugs, and may develop at different rates for different effects.
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Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood
concentration of the drug, and/or administration of an antagonist. The opioid abstinence or
withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation,
rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety,
backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,
diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should
not be abruptly discontinued [see Dosage and Administration (2.3)].
10 OVERDOSAGE
10.1 Clinical Presentation
Acute overdosage with opioids can be manifested by respiratory depression, somnolence
progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted
pupils, and sometimes bradycardia, hypotension and death. The pharmacokinetic characteristics
of DURAGESIC must also be taken into account when treating the overdose. Even in the face of
improvement, continued medical monitoring is required because of the possibility of extended
effects. Deaths due to overdose have been reported with abuse and misuse of DURAGESIC.
10.2 Treatment
Give primary attention to the reestablishment of a patent airway and institution of assisted or
controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the
management of circulatory shock and pulmonary edema accompanying overdose as indicated.
Cardiac arrest or arrhythmias will require advanced life support techniques. Remove all
DURAGESIC systems.
The pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression
from opioid overdose. Since the duration of reversal is expected to be less than the duration of
action of fentanyl, carefully monitor the patient until spontaneous respiration is reliably
reestablished. After DURAGESIC system removal, serum fentanyl concentrations decline
gradually, falling about 50% in approximately 20-27 hours. Therefore, management of an
overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose.
Only administer opioid antagonists in the presence of clinically significant respiratory or
circulatory depression secondary to hydromorphone overdose. In patients who are physically
dependent on any opioid agonist including DURAGESIC, an abrupt or complete reversal of
opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal
syndrome produced will depend on the degree of physical dependence and the dose of the
antagonist administered. Please see the prescribing information for the specific opioid antagonist
for details of their proper use.
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11 DESCRIPTION
DURAGESIC (fentanyl transdermal system) is a transdermal system containing fentanyl. The
chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural
formula is: structural formula
The molecular weight of fentanyl base is 336.5, and the empirical formula is C22H28N2O. The
n-octanol: water partition coefficient is 860:1. The pKa is 8.4.
System Components and Structure
The amount of fentanyl released from each system per hour is proportional to the surface area
(25 mcg/h per 10.5 cm2). The composition per unit area of all system sizes is identical.
Dose*
(mcg/h)
Size
(cm2)
Fentanyl Content
(mg)
12**
5.25
2.1
25
10.5
4.2
50
21
8.4
75
31.5
12.6
100
42
16.8
**Nominal delivery rate per hour
***Nominal delivery rate is 12.5 mcg/hr
DURAGESIC is a rectangular transparent unit comprising a protective liner and two
functional layers. Proceeding from the outer surface toward the surface adhering to skin,
these layers are:
1) a backing layer of polyester/ethyl vinyl acetate film; 2) a drug-in-adhesive layer. Before
use, a protective liner covering the adhesive layer is removed and discarded.
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Protective Liner
Drug Containing Layer
Backing Layer usage illustration
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor.
These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.
12.2 Pharmacodynamics
Central Nervous System Effects
Fentanyl exerts its principal pharmacologic effects on the central nervous system. Central
nervous system effects increase with increasing serum fentanyl concentrations.
In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly
occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the
pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by
stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more
common in ambulatory than in recumbent patients, as is postural syncope.
Ventilatory Effects
In clinical trials of 357 non-opioid tolerant subjects treated with DURAGESIC, 13 subjects
experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than
8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of
hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing
less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in
the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been
received that describe opioid-naive post-operative patients who have experienced clinically
significant hypoventilation and death with DURAGESIC.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations,
especially for patients who have an underlying pulmonary condition or who receive concomitant
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opioids or other CNS drugs associated with hypoventilation. The use of DURAGESIC is
contraindicated in patients who are not tolerant to opioid therapy.
Gastrointestinal Tract and Other Smooth Muscle
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the
gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be
responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract
pressure, some patients with biliary colic may experience worsening rather than relief of pain.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to
be variable, in some cases producing urinary urgency, in others, difficulty in urination.
Cardiovascular Effects
Fentanyl may cause orthostatic hypotension and fainting. Fentanyl may infrequently produce
bradycardia. The incidence of bradycardia in clinical trials with DURAGESIC was less than 1%.
Histamine assays and skin wheal testing in clinical studies indicate that clinically significant
histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically
significant histamine release in dosages up to 50 mcg/kg.
12.3 Pharmacokinetics
Absorption
DURAGESIC is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the
matrix at a nearly constant amount per unit time. The concentration gradient existing between the
matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the
direction of the lower concentration at a rate determined by the matrix and the diffusion of
fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over
the 72-hour application period, each system is labeled with a nominal flux which represents the
average amount of drug delivered to the systemic circulation per hour across average skin.
While there is variation in dose delivered among patients, the nominal flux of the systems (12.5,
25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual
titration of dosage for a given patient.
Following DURAGESIC application, the skin under the system absorbs fentanyl, and a depot of
fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic
circulation. Serum fentanyl concentrations increase gradually following initial DURAGESIC
application, generally leveling off between 12 and 24 hours and remaining relatively constant,
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with some fluctuation, for the remainder of the 72-hour application period. Peak serum
concentrations of fentanyl generally occurred between 20 and 72 hours after initial application
(see Table 6). Serum fentanyl concentrations achieved are proportional to the DURAGESIC
delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first
two system applications. By the end of the second 72-hour application, a steady-state serum
concentration is reached and is maintained during subsequent applications of a patch of the same
size (see Figure 1). Patients reach and maintain a steady-state serum concentration that is
determined by individual variation in skin permeability and body clearance of fentanyl.
After system removal, serum fentanyl concentrations decline gradually, falling about 50% in
approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower
disappearance of the drug from the serum than is seen after an IV infusion, where the apparent
half-life is approximately 7 (range 3-12) hours.
A clinical pharmacology study conducted in healthy adult subjects has shown that the application
of heat over the DURAGESIC system increased mean overall fentanyl exposure by 120% and
average maximum fentanyl level by 61%.
TABLE 6: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST
72-HOUR APPLICATION OF DURAGESIC
Mean (SD) Time to
Mean (SD)
Maximal Concentration
Maximal Concentration
Tmax
Cmax
(h)
(ng/mL)
DURAGESIC 12 mcg/h
28.8 (13.7)
0.38 (0.13)*
DURAGESIC 25 mcg/h
31.7 (16.5)
0.85 (0.26)**
DURAGESIC 50 mcg/h
32.8 (15.6)
1.72 (0.53)**
DURAGESIC 75 mcg/h
35.8 (14.1)
2.32 (0.86)**
DURAGESIC 100 mcg/h
29.9 (13.3)
3.36 (1.28)**
*Cmax values dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers
**Cmax values: Study C-2002-048 dose proportionality study in healthy volunteers
NOTE: After system removal there is continued systemic absorption from residual fentanyl in
the skin so that serum concentrations fall 50%, on average, in approximately
20-27 hours.
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Figure 1 Serum Fentanyl Concentrations
Following Single and Multiple Applications of DURAGESIC 100 mcg/h graph
TABLE 7: RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS
FENTANYL IN PATIENTS
Clearance
Volume of Distribution
Half-Life
(L/h)
VSS
t1/2
Range
(L/kg)
(h)
[70 kg]
Range
Range
Surgical Patients
27 – 75
3 - 8
3 - 12
Hepatically Impaired
3 - 80+
0.8 - 8+
4 - 12+
Patients
Renally Impaired
30 – 78
–
–
Patients
+Estimated
NOTE: Information on volume of distribution and half-life not available for renally impaired
patients.
Distribution
Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug.
Alterations in pH may affect its distribution between plasma and the central nervous system.
Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The
average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8).
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Metabolism
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In
humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl
and other inactive metabolites that do not contribute materially to the observed activity of the
drug.
Excretion
Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in
urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately
9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound
fractions of fentanyl in plasma are estimated to be between 13 and 21%.
Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a
human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from
the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.
Hepatic Impairment
Information on the effect of hepatic impairment on the pharmacokinetics of DURAGESIC is
limited. The pharmacokinetics of DURAGESIC delivering 50 µg/hour of fentanyl for 72 hours
was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8),
Cmax and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.
Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination
of DURAGESIC, hepatic impairment would be expected to have significant effects on the
pharmacokinetics of DURAGESIC. Avoid use of DURAGESIC in patients with severe hepatic
impairment [see Dosing and Administration (2.2), Warnings and Precautions (5.12) and Use in
Specific Populations (8.6)].
Renal Impairment
Information on the effect of renal impairment on the pharmacokinetics of DURAGESIC is
limited. The pharmacokinetics of intravenous injection of 25 µg/kg fentanyl was evaluated in
patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea
nitrogen level and fentanyl clearance was found.
Because there is in-vivo evidence of renal contribution to the elimination of DURAGESIC, renal
impairment would be expected to have significant effects on the pharmacokinetics of
DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal impairment [see
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosing and Administration (2.2), Warnings and Precautions (5.13) and Use in Specific
Populations (8.7)].
Pediatric Use
In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations
were approximately twice as high as that of adult patients. In older pediatric patients, the
pharmacokinetic parameters were similar to that of adults. However, these findings have been
taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric
patients (2 years of age and older). For pediatric dosing information, refer to [see Dosing and
Administration (2.2)].
Geriatric Use
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced
clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the
active substance than younger patients. A study conducted with the DURAGESIC fentanyl
transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ
significantly from young adult subjects, although peak serum concentrations tended to be lower
and mean half-life values were prolonged to approximately 34 hours. In this study, a single
DURAGESIC 100 μg/hour patch was applied to a skin site on the upper outer arm in a group of
healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The
mean Cmax and AUC∞ values were approximately 8% lower and 7% higher, respectively, in the
elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC∞
was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%,
respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects
18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.4) and Use
in Specific Populations (8.5)].
Drug Interactions
The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven
healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo
for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by
one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at
5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was
administered to counteract the side effects of fentanyl. The results suggested that ritonavir might
decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
fentanyl AUC0-∞. Coadministration of ritonavir in patients receiving DURAGESIC has not been
studied; however, an increase in fentanyl AUC is expected [see Box Warning and Warnings and
Precautions (5.7) and Drug Interactions (7.1)].
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system
(CYP3A4), therefore, potential interactions may occur when DURAGESIC is given concurrently
with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4
activity may reduce the efficacy of DURAGESIC. The concomitant use of transdermal fentanyl
with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin,
clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem,
erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an
increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects
and may cause potentially fatal respiratory depression. Carefully monitor patients receiving
DURAGESIC and any CYP3A4 inhibitor for signs of respiratory depression for an extended
period of time and adjust the dosage if warranted [see Box Warning and Warnings and
Precautions (5.7)].
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an
increased incidence of tumors at subcutaneous doses up to 33 µg/kg/day in males or
100 µg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the
100 mcg/h patch based on AUC0-24h comparison).
Mutagenesis
There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary
rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the
human lymphocyte and CHO chromosomal aberration in-vitro assays.
Impairment of Fertility
The potential effects of fentanyl on male and female fertility were examined in the rat model via
two separate experiments. In the male fertility study, male rats were treated with fentanyl (0,
0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating;
female rats were not treated. In the female fertility study, female rats were treated with fentanyl
(0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating
until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both
studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily
human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In a separate study, a single
daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses
of 0.3 times the human dose for a period of 12 days.
14 CLINICAL STUDIES
DURAGESIC as therapy for pain due to cancer has been studied in 153 patients. In this patient
population, DURAGESIC has been administered in doses of 25 µg/h to 600 µg/h. Individual
patients have used DURAGESIC continuously for up to 866 days. At one month after initiation
of DURAGESIC therapy, patients generally reported lower pain intensity scores as compared to
a prestudy analgesic regimen of oral morphine.
The duration of DURAGESIC use varied in cancer patients; 56% of patients used DURAGESIC
for over 30 days, 28% continued treatment for more than 4 months, and 10% used DURAGESIC
for more than 1 year.
In the pediatric population, the safety of DURAGESIC has been evaluated in 289 patients with
chronic pain 2-18 years of age. The duration of DURAGESIC use varied; 20% of pediatric
patients were treated for ≤ 15 days; 46% for 16-30 days; 16% for 31-60 days; and 17% for at
least 61 days. Twenty-five patients were treated with DURAGESIC for at least 4 months and
9 patients for more than 9 months.
16 HOW SUPPLIED/STORAGE AND HANDLING
DURAGESIC (fentanyl transdermal system) is supplied in cartons containing 5 individually
packaged systems. See chart for information regarding individual systems.
DURAGESIC Dose
System Size
Fentanyl
NDC
(mcg/h)
(cm2)
Content
Number
(mg)
DURAGESIC-12*
5.25
2.1
50458-090-05
DURAGESIC-25
10.5
4.2
50458-091-05
DURAGESIC-50
21
8.4
50458-092-05
DURAGESIC-75
31.5
12.6
50458-093-05
DURAGESIC-100
42
16.8
50458-094-05
*This lowest dosage is designated as 12 mcg/h (however, the actual dosage is 12.5 mcg/h) to distinguish it from a
125 mcg/h dosage that could be prescribed by using multiple patches.
Store in original unopened pouch. Store up to 25°C (77°F); excursions permitted to 15 - 30°C
(59 - 86°F).
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide and Instructions for Use)
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Provide patients receiving DURAGESIC patches the following information:
• DURAGESIC patches contain fentanyl, an opioid pain medicine that can cause serious
breathing problems and death, especially if used in the wrong way and therefore should
be taken only as directed. Instruct patients to call their doctor immediately or seek
emergency medical help if they experience breathing problems while taking
DURAGESIC.
• DURAGESIC contains fentanyl which has a high potential for abuse. Instruct patients,
family members, and caregivers to protect DURAGESIC from theft or misuse in the
work or home environment.
• Instruct patients to never give DURAGESIC to anyone other than the individual for
whom it was prescribed because of the risk of death or other serious medical problems to
that person for whom it was not intended.
• Advise patients never to change the dose of DURAGESIC or the number of patches
applied to the skin unless instructed to do so by the prescribing healthcare professional.
• Warn patients of the potential for temperature-dependent increases in fentanyl release
from the patch that could result in an overdose of fentanyl. Instruct patients to contact
their healthcare provider if they develop a high fever. Instruct patients to:
•
avoid strenuous exertion that can increase body temperature while wearing
the patch
•
avoid exposing the DURAGESIC application site and surrounding area to
direct external heat sources including heating pads, electric blankets,
sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and
heated water beds.
• Keep DURAGESIC in a secure place out of the reach of children due to the high risk of
fatal respiratory depression. DURAGESIC can be accidentally transferred to children.
Instruct patients to take special precautions to avoid accidental contact when holding or
caring for children.
• If the patch dislodges and accidentally sticks to the skin of another person, to
immediately take the patch off, wash the exposed area with water and seek medical
attention for the accidentally exposed individual as accidental exposure may lead to death
or other serious medical problems.
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• To properly disposal of used and unneeded, unused DURAGESIC, remove them from
their pouches, fold them so that the adhesive side of the patch adheres to itself, and flush
them down the toilet.
• DURAGESIC may impair mental and/or physical ability required for the performance of
potentially hazardous tasks (e.g., driving, operating machinery). Instruct patients to
refrain from any potentially dangerous activity when starting on DURAGESIC or when
their dose is being adjusted, until it is established that they have not been adversely
affected.
• Advise women of childbearing potential who become, or are planning to become
pregnant, to consult a healthcare provider prior to initiating or continuing therapy with
DURAGESIC.
• Instruct patients not to use alcohol or other CNS depressants (e.g. sleep medications,
tranquilizers) while using DURAGESIC because dangerous additive effects may occur,
resulting in serious injury or death.
• Advise patients of the potential for severe constipation.
• When no longer needed, DURAGESIC should not be stopped abruptly to avoid the risk
of precipitating withdrawal symptoms.
Manufactured by:
ALZA Corporation
Vacaville, CA 95688
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Janssen Pharmaceuticals, Inc. 2009
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
DURAGESIC® (Dur-ah-GEE-zik)
(fentanyl) Transdermal System, CII
Medication Guide
DURAGESIC® (Dur-ah-GEE-zik)
(fentanyl) Transdermal System, CII
DURAGESIC® is:
A strong prescription pain medicine that contains an opioid (narcotic) that is used to treat moderate to
severe around-the-clock pain, in people who are already regularly using opioid pain medicine.
Important information about DURAGESIC®:
Get emergency help right away if you use too much DURAGESIC® (overdose). DURAGESIC®
overdose can cause life threatening breathing problems that can lead to death.
Never give anyone else your DURAGESIC®. They could die from using it. Store DURAGESIC® away
from children and in a safe place to prevent stealing or abuse. Selling or giving away DURAGESIC®
is against the law.
Do not use DURAGESIC® if you have:
severe asthma, trouble breathing, or other lung problems.
a bowel blockage or have narrowing of the stomach or intestines.
Before applying DURAGESIC®, tell your healthcare provider if you have a history of:
head injury, seizures
● liver, kidney, thyroid problems
problems urinating
● pancreas or gallbladder problems
abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you:
have a fever
are pregnant or planning to become pregnant. DURAGESIC® may harm your unborn baby.
are breastfeeding. DURAGESIC® passes into breast milk and may harm your baby.
are taking prescription or over-the-counter medicines, vitamins, or herbal supplements.
When using DURAGESIC®:
Do not change your dose. Apply DURAGESIC® exactly as prescribed by your healthcare provider.
See the detailed Instructions for Use for information about how to apply and dispose of the
DURAGESIC® patch.
Do not wear more than 1 patch at the same time unless your healthcare provider tells you to.
Call your healthcare provider if the dose you are using does not control your pain.
Do not stop using DURAGESIC® without talking to your healthcare provider.
While using DURAGESIC® Do Not:
Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated waterbeds, or
tanning lamps, or engage in exercise that increases your body temperature. These can cause an
overdose that can lead to death.
Drive or operate heavy machinery, until you know how DURAGESIC® affects you. DURAGESIC® can
make you sleepy, dizzy, or lightheaded.
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
The possible side effects of DURAGESIC® are:
constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, itching,
redness, or rash where the patch is applied. Call your healthcare provider if you have any of these
symptoms and they are severe.
Get emergency medical help if you have:
trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or
throat, extreme drowsiness, or you are feeling faint.
These are not all the possible side effects of DURAGESIC®. Call your doctor for medical advice about
side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to
dailymed.nlm.nih.gov
Manufactured by: Alza Corporation, Vacaville, CA 95688; Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, www.Duragesic.com or
call 1-800-526-7736
Reference ID: 3380191
This Medication Guide has been approved by the U.S. FDA. Issue: July 2012
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DURAGESIC (Dur-ah-GEE-zik)
(Fentanyl Transdermal System) CII
Instructions for Applying a DURAGESIC patch
Protective Liner
Drug Containing Layer
Backing Layer usage illustration
Before Applying DURAGESIC
Each DURAGESIC patch is sealed in its own protective
pouch. Do not remove a DURAGESIC patch from the
pouch until you are ready to use it.
Do not use a DURAGESIC patch if the pouch seal is
broken or the patch is cut, damaged or changed in any
way.
DURAGESIC patches are available in 5 different doses
and patch sizes. Make sure you have the right dose patch
or patches that have been prescribed for you.
Reference ID: 3380191
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Applying a DURAGESIC Patch
1. Skin Areas Where the DURAGESIC Patch May Be
Figure 1 usage illustration
Applied:
For adults:
Put the patch on the chest, back, flank (sides of the waist),
or upper arm in a place where there is no hair (see Figures
Figure 2 usage illustration
1-4).
For children (and adults with mental impairment):
Put the patch on the upper back (see Figure 2). This
Figure 3 usage illustration
will lower the chances that the child will remove the patch
and put it in their mouth.
For adults and children
Figure 4usage illustration
Do not put a DURAGESIC patch on skin that is very
oily, burned, broken out, cut, irritated, or damaged in any
way.
Avoid sensitive areas or those that move around a lot. If
Figure 5usage illustration
there is hair, do not shave (shaving irritates the skin).
Instead, clip hair as close to the skin as possible (see
Figure 5).
Talk to your doctor if you have questions about skin
application sites.
2. Prepare to Apply a DURAGESIC Patch:
Choose the time of day that is best for you to apply
DURAGESIC . Change it at about the same time of day
(3 days or 72 hours after you apply the patch) or as
directed by your doctor.
Do not wear more than one DURAGESIC patch at a time
unless your doctor tells you to do so. Before putting on a
new DURAGESIC patch, remove the patch you have
been wearing.
Clean the skin area with clear water only. Pat skin
completely dry. Do not use anything on the skin such as
soaps, lotions, oils, or alcohol before the patch is applied.
3. Open the Pouch: Fold and tear at slit, or cut at slit taking
Figure 6
Reference ID: 3380191
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
care so as not to cut the patch, and remove the DURAGESIC
patch. Each DURAGESIC patch is sealed in its own
protective pouch. Do not remove the DURAGESIC patch
from the pouch until you are ready to use it (see Figure 6).
4. Peel: Peel off both parts of the protective liner from the patch.
Each DURAGESIC patch has a clear plastic backing that
can be peeled off in two pieces. This covers the sticky side of
the patch. Carefully peel this backing off. Throw the clear
plastic backing away. Touch the sticky side of the
DURAGESIC patch as little as possible (see Figure 7).
usage illustration
Reference ID: 3380191
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Press: Press the patch onto the chosen skin site with the
Figure 8 usage illustration
palm of your hand and hold there for at least 30
seconds (see Figure 8). Make sure it sticks well, especially
at the edges.
DURAGESIC may not stick to all patients. You need
to check the patches often to make sure that they are
sticking well to the skin.
If the patch falls off right away after applying, throw it
away and put a new one on at a different skin site (see
Disposing a DURAGESIC Patch).
If you have a problem with the patch not sticking
o Apply first aid tape only to the edges of the
patch.
o If you continue to have problems with the
patch sticking, you may cover the patch
with Bioclusive™ or Tegaderm™. These
are special see-through adhesive dressings.
Never cover a DURAGESIC patch with
any other bandage or tape. Remove the
backing from the Bioclusive™ or
Tegaderm™ dressing and place it carefully
over the DURAGESIC patch, smoothing it
over the patch and your skin.
If your patch falls off later, but before 3 days (72
hours) of use, discard it properly (see Disposing a
DURAGESIC patch) and put a new one on at a
different skin site. Be sure to let your doctor know
that this has happened, and do not replace the new
patch until 3 days (72 hours) after you put it on (or
as directed by your doctor).
6. Wash your hands when you have finished applying a
Reference ID: 3380191
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DURAGESIC patch.
7. Remove a DURAGESIC patch after wearing it for 3 days
(72 hours) (see “Disposing a DURAGESIC Patch”).
Choose a different place on the skin to apply a new
DURAGESIC patch and repeat Steps 2 through 6.
Do not apply the new patch to the same place as the last
one.
Water and DURAGESIC
You can bathe, swim or shower while you are wearing a
DURAGESIC patch. If the patch falls off before 3 days
(72 hours) after application, discard it properly (see
Disposing a DURAGESIC Patch) and put a new one on at
a different skin site. Be sure to let your doctor know that
this has happened, and do not replace the new patch until 3
days (72 hours) after you put it on (or as directed by your
doctor).
Disposing a DURAGESIC Patch
Figure 9 usage illustration
Fold the used DURAGESIC patch in half so that the
sticky side sticks to itself (Figure 9). Flush the used
DURAGESIC down the toilet right away (Figure 10).
A used DURAGESIC patch CAN be VERY dangerous
for or even lead to death in babies, children, pets, and
Figure 10 usage illustration
adults who have not been prescribed DURAGESIC .
Throw away any DURAGESIC patches that are left over
from your prescription as soon as they are no longer
needed. Remove the leftover patches from their protective
pouch and remove the protective liner. Fold the patches
in half with the sticky sides together, and flush the
patches down the toilet. Do not flush the pouch or the
protective liner down the toilet. These items can be thrown
away in a trashcan.
BioclusiveTM is a trademark of Ethicon, Inc.
TegadermTM is a trademark of 3M
Reference ID: 3380191
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx Only
Manufactured by:
Manufactured for:
ALZA Corporation
Janssen Pharmaceuticals, Inc.
Vacaville, CA 95688
Titusville, NJ 08560
©Janssen Pharmaceuticals, Inc. 2009
October 2011
Insert new code
Reference ID: 3380191
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PMS 347
PMS 347
PMS 347
PMS 347
PMS 347 labeling illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:59.522908
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019813s060lblcorrection.pdf', 'application_number': 19813, 'submission_type': 'SUPPL ', 'submission_number': 60}
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_______________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRILOSEC safely and effectively. See full prescribing information for
PRILOSEC.
PRILOSEC (omeprazole) delayed-release capsules
PRILOSEC (omeprazole magnesium) for delayed-release oral suspension
INITIAL U.S. APPROVAL: 1989
-------------------------RECENT MAJOR CHANGES----------------------------
Warnings and Precautions, Interactions with Diagnostic
Investigations for Neuroendocrine Tumors (5.8)
03/2014
Indications and Usage, Treatment of Gastroesophageal Reflux
Disease (GERD) (adults and pediatric patients) (1.3)
12/2014
Dosage and Administration, Maintenance of Healing of
Erosive Esophagitis (2.5)
12/2014
Warnings and Precautions, Acute Interstitial Nephritis (5.3)
12/2014
Warnings and Precautions, Cyanocobalamin (vitamin B-12)
Deficiency (5.4)
12/2014
--------------------------INDICATIONS AND USAGE----------------------------
PRILOSEC is a proton pump inhibitor indicated for:
•
Treatment in adults of duodenal ulcer (1.1) and gastric ulcer (1.2)
•
Treatment in adults and children of gastroesophageal reflux disease
(GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4)
•
Pathologic Hypersecretory Conditions (1.5)
The safety and effectiveness of PRILOSEC in pediatric patients <1 year of
age have not been established. (8.4)
-----------------------DOSAGE AND ADMINISTRATION----------------------
Indication
Omeprazole Dose
Frequency
Treatment of Active
Duodenal Ulcer (2.1)
20 mg
Once daily for 4 weeks. Some
patients may require an
additional 4 weeks
•
Acute interstitial nephritis has been observed in patients taking PPIs.
(5.3)
•
Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g.,
longer than 3 years) may lead to malabsorption or a deficiency of
cyanocobalamin. (5.4)
•
PPI therapy may be associated with increased risk of Clostridium
difficile associated diarrhea. (5.5)
•
Avoid concomitant use of PRILOSEC with clopidogrel. (5.6)
•
Bone Fracture: Long-term and multiple daily dose PPI therapy may be
associated with an increased risk for osteoporosis-related fractures of the
hip, wrist or spine. (5.7)
•
Hypomagnesemia has been reported rarely with prolonged treatment
with PPIs. (5.8)
•
Avoid concomitant use of PRILOSEC with St. John’s Wort or rifampin
due to the potential reduction in omeprazole concentrations. (5.9, 7.3)
•
Interactions with diagnostic investigations for Neuroendocrine Tumors:
Increases in intragastric pH may result in hypergastrinemia and
enterochromaffin-like cell hyperplasia and increased Choromogranin A
levels which may interfere with diagnostic investigations for
neuroendocrine tumors. (5.10, 12.2)
-------------------------------ADVERSE REACTIONS--------------------------
Adults: Most common adverse reactions in adults (incidence ≥ 2%) are
•
Headache, abdominal pain, nausea, diarrhea, vomiting, and
flatulence (6)
Pediatric patients (1 to 16 years of age):
Safety profile similar to that in adults, except that respiratory system
events and fever were the most frequently reported reactions in pediatric
studies. (8.4)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS--------------------------
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
Triple Therapy:
PRILOSEC
20 mg
Each drug twice daily for 10
Amoxicillin
1000 mg
days
Clarithromycin
500 mg
Dual Therapy:
PRILOSEC
40 mg
Once daily for 14 days
Clarithromycin
500 mg
Three times daily for 14 days
Gastric Ulcer (2.3)
40 mg
Once daily for 4 to 8 weeks
GERD (2.4)
20 mg
Once daily for 4 to 8 weeks
Maintenance of Healing of
Erosive Esophagitis (2.5)
20 mg
Once daily*
Pathological Hypersecretory
Conditions (2.6)
60 mg (varies with
individual patient)
Once daily
Pediatric Patients
(1 to 16 years of age) (2.7)
GERD** And
Maintenance of Healing of
Erosive Esophagitis
Weight
Dose
5 < 10 kg
5 mg
10< 20 kg 10 mg
> 20 kg
20 mg
Once daily
*studied for 12 months
**4 to 8 weeks
----------------------DOSAGE FORMS AND STRENGTHS--------------------
•
PRILOSEC Delayed-Release Capsules, 10 mg, 20 mg and 40 mg (3)
•
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg (3)
---------------------------CONTRAINDICATIONS-------------------------------
Known hypersensitivity to any component of the formulation or substituted
benzimidazoles (angioedema and anaphylaxis have occurred). (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
•
Symptomatic response does not preclude the presence of gastric
malignancy. (5.1)
•
Atrophic gastritis: has been noted with long-term therapy. (5.2)
•
Atazanavir and nelfinavir: PRILOSEC reduces plasma levels of
atazanavir and nelfinavir. Concomitant use is not recommended. (7.1)
•
Saquinavir: PRILOSEC increases plasma levels of saquinavir. Monitor
for toxicity and consider dose reduction of saquinavir. (7.1)
•
May interfere with drugs for which gastric pH affects bioavailability
(e.g., ketoconazole, iron salts, erlotinib, ampicillin esters, digoxin and
mycophenolate mofetil). Patients treated with PRILOSEC and
digoxin may need to be monitored for increases in digoxin toxicity. (7.2)
•
Clopidogrel: PRILOSEC decreases exposure to the active metabolite of
clopidogrel. (7.3, 12.3)
•
Cilostazol: PRILOSEC increases systemic exposure of cilostazol and
one of its active metabolites. Consider dose reduction of cilostazol. (7.3)
•
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin,
phenytoin, cyclosporine, disulfiram, benzodiazepines): PRILOSEC can
prolong their elimination. Monitor and determine need for dose
adjustments. (7.3)
•
Patients treated with proton pump inhibitors and warfarin may need to
be monitored for increases in INR and prothrombin time. (7.3)
•
Combined inhibitor of CYP2C19 and 3A4 (e.g. voriconazole) may raise
omeprazole levels. (7.3)
•
Tacrolimus: PRILOSEC may increase serum levels of tacrolimus. (7.4)
•
Methotrexate: PRILOSEC may increase serum levels of methotrexate.
(7.7)
------------------------USE IN SPECIFIC POPULATIONS----------------------
•
Pregnancy: Based on animal data may cause fetal harm. (8.1)
•
Patients with hepatic impairment:
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis. (12.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
Approved Medication Guide.
REVISED: 12/2014
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Duodenal Ulcer (adults)
1.2 Gastric Ulcer (adults)
1.3 Treatment of Gastroesophageal Reflux Disease (GERD)
(adults and pediatric patients)
1.4 Maintenance of Healing of Erosive Esophagitis (adults and
pediatric patients)
1.5 Pathological Hypersecretory Conditions (adults)
2
DOSAGE AND ADMINISTRATION
2.1 Short-Term Treatment of Active Duodenal Ulcer
2.2 H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
2.3 Gastric Ulcer
2.4 Gastroesophageal Reflux Disease (GERD)
2.5 Maintenance of Healing of Erosive Esophagitis
2.6 Pathological Hypersecretory Conditions
2.7 Pediatric Patients
2.8 Alternative Administration Options
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Concomitant Gastric Malignancy
5.2 Atrophic Gastritis
5.3 Acute Interstitial Nephritis
5.4 Cyanocobalamin (vitamin B-12) Deficiency
5.5 Clostridium difficile associated diarrhea
5.6 Interaction with Clopidogrel
5.7 Bone Fracture
5.8 Hypomagnesemia
5.9 Concomitant Use of PRILOSEC with St. John’s Wort or
rifampin
5.10 Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
5.11 Concomitant use of PRILOSEC with Methotrexate
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience with PRILOSEC Monotherapy
6.2 Clinical Trials Experience with PRILOSEC in Combination
Therapy for H. pylori Eradication
6.3 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Interference with Antiretroviral Therapy
7.2 Drugs for Which Gastric pH Can Affect Bioavailability
7.3
Effects on Hepatic Metabolism/Cytochrome P-450 Pathways
7.4 Tacrolimus
7.5 Interactions with Investigations of Neuroendocrine Tumors
7.6 Combination Therapy with Clarithromycin
7.7 Methotrexate
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Asian Population
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
14.2 Gastric Ulcer
14.3 Gastroesophageal Reflux Disease (GERD)
14.4 Erosive Esophagitis
14.5 Pathological Hypersecretory Conditions
14.6 Pediatric GERD
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1
Duodenal Ulcer (adults)
PRILOSEC is indicated for short-term treatment of active duodenal
ulcer in adults. Most patients heal within four weeks. Some patients
may require an additional four weeks of therapy.
PRILOSEC in combination with clarithromycin and amoxicillin, is
indicated for treatment of patients with H. pylori infection and
duodenal ulcer disease (active or up to 1-year history) to eradicate H.
pylori in adults.
PRILOSEC in combination with clarithromycin is indicated for
treatment of patients with H. pylori infection and duodenal ulcer
disease to eradicate H. pylori in adults.
Eradication of H. pylori has been shown to reduce the risk of
duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage
and Administration (2)].
Among patients who fail therapy, PRILOSEC with clarithromycin is
more likely to be associated with the development of clarithromycin
resistance as compared with triple therapy. In patients who fail
therapy, susceptibility testing should be done. If resistance to
clarithromycin is demonstrated or susceptibility testing is not
possible, alternative antimicrobial therapy should be instituted [see
Microbiology section (12.4)], and the clarithromycin package insert,
Microbiology section.
1.2
Gastric Ulcer (adults)
PRILOSEC is indicated for short-term treatment (4-8 weeks) of active
benign gastric ulcer in adults [see Clinical Studies (14.2)].
1.3
Treatment of Gastroesophageal Reflux Disease
(GERD) (adults and pediatric patients)
Symptomatic GERD
PRILOSEC is indicated for the treatment of heartburn and other
symptoms associated with GERD in pediatric patients and adults for
up to 4 weeks.
Erosive Esophagitis
PRILOSEC is indicated for the short-term treatment (4-8 weeks) of
erosive esophagitis that has been diagnosed by endoscopy in pediatric
patients and adults [see Clinical Studies (14.4)].
3
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of PRILOSEC used for longer than 8 weeks in these
patients has not been established. If a patient does not respond to 8
weeks of treatment, an additional 4 weeks of treatment may be given.
If there is recurrence of erosive esophagitis or GERD symptoms (eg,
heartburn), additional 4-8 week courses of omeprazole may be
considered.
1.4
Maintenance of Healing of Erosive Esophagitis
(adults and pediatric patients)
PRILOSEC is indicated to maintain healing of erosive esophagitis in
pediatric patients and adults.
Controlled studies do not extend beyond 12 months [see Clinical
Studies (14.4)].
1.5
Pathological Hypersecretory Conditions (adults)
PRILOSEC is indicated for the long-term treatment of pathological
hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple
endocrine adenomas and systemic mastocytosis) in adults.
2
DOSAGE AND ADMINISTRATION
PRILOSEC Delayed-Release Capsules should be taken before eating.
In the clinical trials, antacids were used concomitantly with
PRILOSEC.
Patients should be informed that the PRILOSEC Delayed-Release
Capsule should be swallowed whole.
For patients unable to swallow an intact capsule, alternative
administration options are available [see Dosage and Administration
(2.8)].
2.1
Short-Term Treatment of Active Duodenal Ulcer
The recommended adult oral dose of PRILOSEC is 20 mg once daily.
Most patients heal within four weeks. Some patients may require an
additional four weeks of therapy.
2.2
H. pylori Eradication for the Reduction of the Risk of
Duodenal Ulcer Recurrence
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin) — The
recommended adult oral regimen is PRILOSEC 20 mg plus
clarithromycin 500 mg plus amoxicillin 1000 mg each given twice
daily for 10 days. In patients with an ulcer present at the time of
initiation of therapy, an additional 18 days of PRILOSEC 20 mg once
daily is recommended for ulcer healing and symptom relief.
Dual Therapy (PRILOSEC/clarithromycin) — The recommended
adult oral regimen is PRILOSEC 40 mg once daily plus
clarithromycin 500 mg three times daily for 14 days. In patients with
an ulcer present at the time of initiation of therapy, an additional 14
4
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
days of PRILOSEC 20 mg once daily is recommended for ulcer
healing and symptom relief.
2.3
Gastric Ulcer
The recommended adult oral dose is 40 mg once daily for 4-8 weeks.
2.4
Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients with
symptomatic GERD and no esophageal lesions is 20 mg daily for up
to 4 weeks. The recommended adult oral dose for the treatment of
patients with erosive esophagitis and accompanying symptoms due to
GERD is 20 mg daily for 4 to 8 weeks.
2.5
Maintenance of Healing of Erosive Esophagitis
The recommended adult oral dose is 20 mg daily. Controlled studies
do not extend beyond 12 months [see Clinical Studies (14.4)].
2.6
Pathological Hypersecretory Conditions
The dosage of PRILOSEC in patients with pathological
hypersecretory conditions varies with the individual patient. The
recommended adult oral starting dose is 60 mg once daily. Doses
should be adjusted to individual patient needs and should continue for
as long as clinically indicated. Doses up to 120 mg three times daily
have been administered. Daily dosages of greater than 80 mg should
be administered in divided doses. Some patients with Zollinger-
Ellison syndrome have been treated continuously with PRILOSEC for
more than 5 years.
2.7
Pediatric Patients
For the treatment of GERD and maintenance of healing of erosive
esophagitis, the recommended daily dose for pediatric patients 1 to 16
years of age is as follows:
Patient Weight
Omeprazole Daily Dose
5 < 10 kg
5 mg
10 < 20 kg
10 mg
> 20 kg
20 mg
On a per kg basis, the doses of omeprazole required to heal erosive
esophagitis in pediatric patients are greater than those for adults.
Alternative administrative options can be used for pediatric patients
unable to swallow an intact capsule [see Dosage and Administration
(2.8)].
2.8
Alternative Administration Options
PRILOSEC is available as a delayed-release capsule or as a delayed-
release oral suspension.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
5
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
3
DOSAGE FORMS AND STRENGTHS
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body.
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on the body.
6
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body.
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules.
4
CONTRAINDICATIONS
PRILOSEC Delayed-Release Capsules are contraindicated in patients
with known hypersensitivity to substituted benzimidazoles or to any
component of the formulation. Hypersensitivity reactions may include
anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute
interstitial nephritis, and urticaria [see Adverse Reactions (6)].
For information about contraindications of antibacterial agents
(clarithromycin and amoxicillin) indicated in combination with
PRILOSEC, refer to the CONTRAINDICATIONS section of their
package inserts.
5
WARNINGS AND PRECAUTIONS
5.1
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude
the presence of gastric malignancy.
5.2
Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus
biopsies from patients treated long-term with omeprazole.
5.3
Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs
including PRILOSEC. Acute interstitial nephritis may occur at any
point during PPI therapy and is generally attributed to an idiopathic
hypersensitivity reaction. Discontinue PRILOSEC if acute interstitial
nephritis develops [see Contraindications (4)].
5.4
Cyanocobalamin (vitamin B-12) Deficiency
Daily treatment with any acid-suppressing medications over a long
period of time (e.g., longer than 3 years) may lead to malabsorption of
cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria.
Rare reports of cyanocobalamin deficiency occurring with
acidsuppressing therapy have been reported in the literature. This
diagnosis should be considered if clinical symptoms consistent with
cyanocobalamin deficiency are observed.
5.5
Clostridium difficile associated diarrhea
7
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Published observational studies suggest that PPI therapy like
PRILOSEC may be associated with an increased risk of Clostridium
difficile associated diarrhea, especially in hospitalized patients. This
diagnosis should be considered for diarrhea that does not improve
[see Adverse Reactions (6.2)].
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated.
Clostridium difficile associated diarrhea (CDAD) has been reported
with use of nearly all antibacterial agents. For more information
specific to antibacterial agents (clarithromycin and amoxicillin)
indicated for use in combination with PRILOSEC, refer to
WARNINGS and PRECAUTIONS sections of those package inserts.
5.6
Interaction with Clopidogrel
Avoid concomitant use of PRILOSEC with clopidogrel. Clopidogrel
is a prodrug. Inhibition of platelet aggregation by clopidogrel is
entirely due to an active metabolite. The metabolism of clopidogrel to
its active metabolite can be impaired by use with concomitant
medications, such as omeprazole, that inhibit CYP2C19 activity.
Concomitant use of clopidogrel with 80 mg omeprazole reduces the
pharmacological activity of clopidogrel, even when administered 12
hours apart. When using PRILOSEC, consider alternative anti-platelet
therapy [see Drug Interactions (7.3) and Pharmacokinetics (12.3)].
5.7
Bone Fracture
Several published observational studies suggest that proton pump
inhibitor (PPI) therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as
multiple daily doses, and long-term PPI therapy (a year or longer).
Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated. Patients at risk for
osteoporosis-related fractures should be managed according to
established treatment guidelines [see Dosage and Administration (2)
and Adverse Reactions (6.3)].
5.8
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported
rarely in patients treated with PPIs for at least three months, in most
cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of
hypomagnesemia required magnesium replacement and
discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs
with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), health care professionals may
8
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
consider monitoring magnesium levels prior to initiation of PPI
treatment and periodically [see Adverse Reactions (6.3)].
5.9
Concomitant use of PRILOSEC with St. John’s Wort
or rifampin
Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort
or rifampin) can substantially decrease omeprazole concentrations
[see Drug Interactions (7.3)]. Avoid concomitant use of PRILOSEC
with St. John’s Wort or rifampin.
5.10 Interactions with Diagnostic Investigations for
Neuroendocrine Tumors
Serum chromogranin A (CgA) levels increase secondary to drug-
induced decreases in gastric acidity. The increased CgA level may
cause false positive results in diagnostic investigations for
neuroendocrine tumors. Healthcare providers should temporarily stop
omeprazole treatment at least 14 days before assessing CgA levels
and consider repeating the test if initial CgA levels are high. If serial
tests are performed (e.g. for monitoring), the same commercial
laboratory should be used for testing, as reference ranges between
tests may vary.
5.11 Concomitant use of PRILOSEC with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate
(primarily at high dose; see methotrexate prescribing information)
may elevate and prolong serum levels of methotrexate and/or its
metabolite, possibly leading to methotrexate toxicities. In high-dose
methotrexate administration a temporary withdrawal of the PPI may
be considered in some patients [see Drug Interactions (7.7)].
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience with PRILOSEC
Monotherapy
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The safety data described below reflects exposure to PRILOSEC
Delayed-Release Capsules in 3096 patients from worldwide clinical
trials (465 patients from US studies and 2,631 patients from
international studies). Indications clinically studied in US trials
included duodenal ulcer, resistant ulcer, and Zollinger-Ellison
syndrome. The international clinical trials were double blind and
open-label in design. The most common adverse reactions reported
(i.e., with an incidence rate ≥ 2%) from PRILOSEC-treated patients
enrolled in these studies included headache (6.9%), abdominal pain
(5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and
flatulence (2.7%).
9
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Additional adverse reactions that were reported with an incidence
≥1% included acid regurgitation (1.9%), upper respiratory infection
(1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia
(1.3%), back pain (1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age
was similar to that in patients 65 years of age or less.
The clinical trial safety profile in pediatric patients who received
PRILOSEC Delayed-Release Capsules was similar to that in adult
patients. Unique to the pediatric population, however, adverse
reactions of the respiratory system were most frequently reported in
both the 1 to <2 and 2 to 16 year age groups (75.0% and 18.5%,
respectively). Similarly, fever was frequently reported in the 1 to 2
year age group (33.0%), and accidental injuries were reported
frequently in the 2 to 16 year age group (3.8%) [see Use in Specific
Populations (8.4)].
6.2
Clinical Trials Experience with PRILOSEC in
Combination Therapy for H. pylori Eradication
In clinical trials using either dual therapy with PRILOSEC and
clarithromycin, or triple therapy with PRILOSEC, clarithromycin,
and amoxicillin, no adverse reactions unique to these drug
combinations were observed. Adverse reactions observed were
limited to those previously reported with omeprazole, clarithromycin,
or amoxicillin alone.
Dual Therapy (PRILOSEC/clarithromycin)
Adverse reactions observed in controlled clinical trials using
combination therapy with PRILOSEC and clarithromycin (n = 346)
that differed from those previously described for PRILOSEC alone
were taste perversion (15%), tongue discoloration (2%), rhinitis (2%),
pharyngitis (1%) and flu-syndrome (1%). (For more information on
clarithromycin, refer to the clarithromycin prescribing information,
Adverse Reactions section.)
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)
The most frequent adverse reactions observed in clinical trials using
combination therapy with PRILOSEC, clarithromycin, and
amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%),
and headache (7%). None of these occurred at a higher frequency
than that reported by patients taking antimicrobial agents alone. (For
more information on clarithromycin or amoxicillin, refer to the
respective prescribing information, Adverse Reactions sections.)
6.3
Post-marketing Experience
The following adverse reactions have been identified during post-
approval use of PRILOSEC Delayed-Release Capsules. Because
these reactions are voluntarily reported from a population of uncertain
10
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
size, it is not always possible to reliably estimate their actual
frequency or establish a causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions including anaphylaxis,
anaphylactic shock, angioedema, bronchospasm, interstitial nephritis,
urticaria, (see also Skin below); fever; pain; fatigue; malaise;
Cardiovascular: Chest pain or angina, tachycardia, bradycardia,
palpitations, elevated blood pressure, peripheral edema
Endocrine: Gynecomastia
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon,
fecal discoloration, esophageal candidiasis, mucosal atrophy of the
tongue, stomatitis, abdominal swelling, dry mouth, microscopic
colitis. During treatment with omeprazole, gastric fundic gland
polyps have been noted rarely. These polyps are benign and appear to
be reversible when treatment is discontinued.
Gastroduodenal carcinoids have been reported in patients with ZE
syndrome on long-term treatment with PRILOSEC. This finding is
believed to be a manifestation of the underlying condition, which is
known to be associated with such tumors.
Hepatic: Liver disease including hepatic failure (some fatal), liver
necrosis (some fatal), hepatic encephalopathy hepatocellular disease,
cholestatic disease, mixed hepatitis, jaundice, and elevations of liver
function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
Infections and Infestations: Clostridium difficile associated diarrhea
Metabolism and Nutritional disorders: Hypoglycemia,
hypomagnesemia, with or without hypocalcemia and/or hypokalemia,
hyponatremia, weight gain
Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint
pain, leg pain, bone fracture
Nervous System/Psychiatric: Psychiatric and sleep disturbances
including depression, agitation, aggression, hallucinations, confusion,
insomnia, nervousness, apathy, somnolence, anxiety, and dream
abnormalities; tremors, paresthesia; vertigo
Respiratory: Epistaxis, pharyngeal pain
Skin: Severe generalized skin reactions including toxic epidermal
necrolysis (some fatal), Stevens-Johnson syndrome, and erythema
multiforme; photosensitivity; urticaria; rash; skin inflammation;
pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis
Special Senses: Tinnitus, taste perversion
Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic
neuritis, dry eye syndrome, ocular irritation, blurred vision, double
vision
Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated
serum creatinine, microscopic pyuria, urinary tract infection,
glycosuria, urinary frequency, testicular pain
Hematologic: Agranulocytosis (some fatal), hemolytic anemia,
pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia,
leucocytosis
11
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
DRUG INTERACTIONS
7.1
Interference with Antiretroviral Therapy
Concomitant use of atazanavir and nelfinavir with proton pump
inhibitors is not recommended. Co-administration of atazanavir with
proton pump inhibitors is expected to substantially decrease
atazanavir plasma concentrations and may result in a loss of
therapeutic effect and the development of drug resistance. Co-
administration of saquinavir with proton pump inhibitors is expected
to increase saquinavir concentrations, which may increase toxicity
and require dose reduction.
Omeprazole has been reported to interact with some antiretroviral
drugs. The clinical importance and the mechanisms behind these
interactions are not always known. Increased gastric pH during
omeprazole treatment may change the absorption of the antiretroviral
drug. Other possible interaction mechanisms are via CYP2C19.
Reduced concentrations of atazanavir and nelfinavir
For some antiretroviral drugs, such as atazanavir and nelfinavir,
decreased serum levels have been reported when given together with
omeprazole. Following multiple doses of nelfinavir (1250 mg, twice
daily) and omeprazole (40 mg daily), AUC was decreased by 36%
and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%
respectively for nelfinavir and M8. Following multiple doses of
atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before
atazanavir), AUC was decreased by 94%, C max by 96%, and Cmin by
95%. Concomitant administration with omeprazole and drugs such as
atazanavir and nelfinavir is therefore not recommended.
Increased concentrations of saquinavir
For other antiretroviral drugs, such as saquinavir, elevated serum
levels have been reported, with an increase in AUC by 82%, in Cmax
by 75%, and in Cmin by 106%, following multiple dosing of
saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with
omeprazole 40 mg daily co-administered days 11 to 15. Therefore,
clinical and laboratory monitoring for saquinavir toxicity is
recommended during concurrent use with PRILOSEC. Dose
reduction of saquinavir should be considered from the safety
perspective for individual patients.
There are also some antiretroviral drugs of which unchanged serum
levels have been reported when given with omeprazole.
7.2
Drugs for Which Gastric pH Can Affect
Bioavailability
Due to its effects on gastric acid secretion, omeprazole can reduce the
absorption of drugs where gastric pH is an important determinant of
their bioavailability. Like with other drugs that decrease the
intragastric acidity, the absorption of drugs such as ketoconazole,
12
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF)
can decrease, while the absorption of drugs such as digoxin can
increase during treatment with omeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in
healthy subjects increased the bioavailability of digoxin by 10% (30%
in two subjects). Co-administration of digoxin with PRILOSEC is
expected to increase the systemic exposure of digoxin. Therefore,
patients may need to be monitored when digoxin is taken
concomitantly with PRILOSEC.
Co-administration of omeprazole in healthy subjects and in transplant
patients receiving MMF has been reported to reduce the exposure to
the active metabolite, mycophenolic acid (MPA), possibly due to a
decrease in MMF solubility at an increased gastric pH. The clinical
relevance of reduced MPA exposure on organ rejection has not been
established in transplant patients receiving PRILOSEC and MMF.
Use PRILOSEC with caution in transplant patients receiving MMF
[see Clinical Pharmacology (12.3)].
7.3
Effects on Hepatic Metabolism/Cytochrome P-450
Pathways
Omeprazole can prolong the elimination of diazepam, warfarin and
phenytoin, drugs that are metabolized by oxidation in the liver. There
have been reports of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including omeprazole, and warfarin
concomitantly. Increases in INR and prothrombin time may lead to
abnormal bleeding and even death. Patients treated with proton pump
inhibitors and warfarin may need to be monitored for increases in
INR and prothrombin time.
Although in normal subjects no interaction with theophylline or
propranolol was found, there have been clinical reports of interaction
with other drugs metabolized via the cytochrome P450 system (e.g.,
cyclosporine, disulfiram, benzodiazepines). Patients should be
monitored to determine if it is necessary to adjust the dosage of these
drugs when taken concomitantly with PRILOSEC.
Concomitant administration of omeprazole and voriconazole (a
combined inhibitor of CYP2C19 and CYP3A4) resulted in more than
doubling of the omeprazole exposure. Dose adjustment of omeprazole
is not normally required. However, in patients with Zollinger-Ellison
syndrome, who may require higher doses up to 240 mg/day, dose
adjustment may be considered. When voriconazole (400 mg Q12h x 1
day, then 200 mg x 6 days) was given with omeprazole (40 mg once
daily x 7 days) to healthy subjects, it significantly increased the
steady-state C max and AUC0-24 of omeprazole, an average of 2 times
(90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as
compared to when omeprazole was given without voriconazole.
13
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Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in
doses of 40 mg daily for one week to 20 healthy subjects in cross-
over study, increased Cmax and AUC of cilostazol by 18% and 26%
respectively. C max and AUC of one of its active metabolites, 3,4-
dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were
increased by 29% and 69% respectively. Co-administration of
cilostazol with omeprazole is expected to increase concentrations of
cilostazol and its above mentioned active metabolite. Therefore a
dose reduction of cilostazol from 100 mg twice daily to 50 mg twice
daily should be considered.
Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin)
may lead to decreased omeprazole serum levels. In a cross-over study
in 12 healthy male subjects, St. John’s wort (300 mg three times daily
for 14 days), an inducer of CYP3A4, decreased the systemic exposure
of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC
decreased by 37.5% and 37.9%, respectively) and extensive
metabolisers (Cmax and AUC decreased by 49.6% and 43.9%,
respectively). Avoid concomitant use of St. John’s Wort or rifampin
with omeprazole.
Clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is
metabolized to its active metabolite in part by CYP2C19.
Concomitant use of omeprazole 80 mg results in reduced plasma
concentrations of the active metabolite of clopidogrel and a reduction
in platelet inhibition. Avoid concomitant administration of
PRILOSEC with clopidogrel. When using PRILOSEC, consider use
of alternative anti-platelet therapy [see Pharmacokinetics (12.3)].
There are no adequate combination studies of a lower dose of
omeprazole or a higher dose of clopidogrel in comparison with the
approved dose of clopidogrel.
7.4
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may
increase the serum levels of tacrolimus.
7.5
Interactions with Investigations of Neuroendocrine
Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin-
like cell hyperplasia and increased Chromogranin A levels which may
interfere with investigations for neuroendocrine tumors [see Warnings
and Precautions (5.10) and Clinical Pharmacology (12)].
7.6
Combination Therapy with Clarithromycin
Concomitant administration of clarithromycin with other drugs can
lead to serious adverse reactions due to drug interactions [see
Warnings and Precautions in prescribing information for
clarithromycin]. Because of these drug interactions, clarithromycin is
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contraindicated for co-administration with certain drugs [see
Contraindications in prescribing information for clarithromycin].
7.7
Methotrexate
Case reports, published population pharmacokinetic studies, and
retrospective analyses suggest that concomitant administration of
PPIs and methotrexate (primarily at high dose; see methotrexate
prescribing information) may elevate and prolong serum levels of
methotrexate and/or its metabolite hydroxymethotrexate. However,
no formal drug interaction studies of methotrexate with PPIs have
been conducted [see Warnings and Precautions (5.11)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with PRILOSEC in
pregnant women. Available epidemiologic data fail to demonstrate
an increased risk of major congenital malformations or other adverse
pregnancy outcomes with first trimester omeprazole use.
Teratogenicity was not observed in animal reproduction studies with
administration of oral esomeprazole magnesium in rats and rabbits
with doses about 68 times and 42 times, respectively, an oral human
dose of 40 mg (based on a body surface area basis for a 60 kg
person). However, changes in bone morphology were observed in
offspring of rats dosed through most of pregnancy and lactation at
doses equal to or greater than approximately 34 times an oral human
dose of 40 mg (see Animal Data). Because of the observed effect at
high doses of esomeprazole magnesium on developing bone in rat
studies, PRILOSEC should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Human Data
Four published epidemiological studies compared the frequency of
congenital abnormalities among infants born to women who used
omeprazole during pregnancy with the frequency of abnormalities
among infants of women exposed to H2-receptor antagonists or other
controls.
A population-based retrospective cohort epidemiological study from
the Swedish Medical Birth Registry, covering approximately 99% of
pregnancies, from 1995-99, reported on 955 infants (824 exposed
during the first trimester with 39 of these exposed beyond first
trimester, and 131 exposed after the first trimester) whose mothers
used omeprazole during pregnancy. The number of infants exposed in
utero to omeprazole that had any malformation, low birth weight, low
Apgar score, or hospitalization was similar to the number observed in
this population. The number of infants born with ventricular septal
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Reference ID: 3675793
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defects and the number of stillborn infants was slightly higher in the
omeprazole-exposed infants than the expected number in this
population.
A population-based retrospective cohort study covering all live births
in Denmark from 1996-2009, reported on 1,800 live births whose
mothers used omeprazole during the first trimester of pregnancy and
837, 317 live births whose mothers did not use any proton pump
inhibitor. The overall rate of birth defects in infants born to mothers
with first trimester exposure to omeprazole was 2.9% and 2.6% in
infants born to mothers not exposed to any proton pump inhibitor
during the first trimester.
A retrospective cohort study reported on 689 pregnant women
exposed to either H2-blockers or omeprazole in the first trimester
(134 exposed to omeprazole) and 1,572 pregnant women unexposed
to either during the first trimester. The overall malformation rate in
offspring born to mothers with first trimester exposure to omeprazole,
an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1%
respectively.
A small prospective observational cohort study followed 113 women
exposed to omeprazole during pregnancy (89% first trimester
exposures). The reported rate of major congenital malformations was
4% in the omeprazole group, 2% in controls exposed to non-
teratogens, and 2.8% in disease-paired controls. Rates of spontaneous
and elective abortions, preterm deliveries, gestational age at delivery,
and mean birth weight were similar among the groups.
Several studies have reported no apparent adverse short-term effects
on the infant when single dose oral or intravenous omeprazole was
administered to over 200 pregnant women as premedication for
cesarean section under general anesthesia.
Animal Data
Reproductive studies conducted with omeprazole in rats at oral doses
up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on
a body surface area basis) and in rabbits at doses up to 69 mg/kg/day
(about 34 times an oral human dose of 40 mg on a body surface area
basis) did not disclose any evidence for a teratogenic potential of
omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1
mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a
body surface area basis) produced dose-related increases in embryo-
lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-
related embryo/fetal toxicity and postnatal developmental toxicity
were observed in offspring resulting from parents treated with
omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times an oral
human doses of 40 mg on a body surface area basis).
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Reference ID: 3675793
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Reproduction studies have been performed with esomeprazole
magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times
an oral human dose of 40 mg on a body surface area basis) and in
rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral
human dose of 40 mg on a body surface area basis) and have revealed
no evidence of impaired fertility or harm to the fetus due to
esomeprazole magnesium.
A pre- and postnatal developmental toxicity study in rats with
additional endpoints to evaluate bone development was performed
with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day
(about 3.4 to 68 times an oral human dose of 40 mg on a body surface
area basis). Neonatal/early postnatal (birth to weaning) survival was
decreased at doses equal to or greater than 138 mg/kg/day (about 34
times an oral human dose of 40 mg on a body surface area basis).
Body weight and body weight gain were reduced and neurobehavioral
or general developmental delays in the immediate post-weaning
timeframe were evident at doses equal to or greater than 69
mg/kg/day (about 17 times an oral human dose of 40 mg on a body
surface area basis). In addition, decreased femur length, width and
thickness of cortical bone, decreased thickness of the tibial growth
plate and minimal to mild bone marrow hypocellularity were noted at
doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral
human dose of 40 mg on a body surface area basis). Physeal dysplasia
in the femur was observed in offspring of rats treated with oral doses
of esomeprazole magnesium at doses equal to or greater than 138
mg/kg/day (about 34 times an oral human dose of 40 mg on a body
surface area basis).
Effects on maternal bone were observed in pregnant and lactating rats
in the pre- and postnatal toxicity study when esomeprazole
magnesium was administered at oral doses of 14 to 280 mg/kg/day
(about 3.4 to 68 times an oral human dose of 40 mg on a body surface
area basis). When rats were dosed from gestational day 7 through
weaning on postnatal day 21, a statistically significant decrease in
maternal femur weight of up to 14% (as compared to placebo
treatment) was observed at doses equal to or greater than 138
mg/kg/day (about 34 times an oral human dose of 40 mg on a body
surface area basis).
A pre- and postnatal development study in rats with esomeprazole
strontium (using equimolar doses compared to esomeprazole
magnesium study) produced similar results in dams and pups as
described above.
8.3
Nursing Mothers
Omeprazole is present in human milk. Omeprazole concentrations
were measured in breast milk of a woman following oral
administration of 20 mg. The peak concentration of omeprazole in
breast milk was less than 7% of the peak serum concentration. This
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Reference ID: 3675793
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concentration would correspond to 0.004 mg of omeprazole in 200
mL of milk. Caution should be exercised when PRILOSEC is
administered to a nursing woman.
8.4
Pediatric Use
Use of PRILOSEC in pediatric and adolescent patients 1 to 16 years
of age for the treatment of GERD and maintenance of healing of
erosive esophagitis is supported by a) extrapolation of results from
adequate and well-controlled studies that supported the approval of
PRILOSEC for adults, and b) safety and pharmacokinetic studies
performed in pediatric and adolescent patients [see Clinical
Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic
information (12.3) and Dosage and Administration (2), Adverse
Reactions (6.1) and Clinical Studies (14.6)]. The safety and
effectiveness of PRILOSEC for the treatment of GERD in patients <1
year of age have not been established. The safety and effectiveness of
PRILOSEC for other pediatric uses have not been established.
Juvenile Animal Data
In a juvenile rat toxicity study, esomeprazole was administered with
both magnesium and strontium salts at oral doses about 34 to 68 times
a daily human dose of 40 mg based on body surface area. Increases
in death were seen at the high dose, and at all doses of esomeprazole,
there were decreases in body weight, body weight gain, femur weight
and femur length, and decreases in overall growth [see Nonclinical
Toxicology (13.2)].
8.5
Geriatric Use
Omeprazole was administered to over 2000 elderly individuals (≥ 65
years of age) in clinical trials in the U.S. and Europe. There were no
differences in safety and effectiveness between the elderly and
younger subjects. Other reported clinical experience has not
identified differences in response between the elderly and younger
subjects, but greater sensitivity of some older individuals cannot be
ruled out.
Pharmacokinetic studies have shown the elimination rate was
somewhat decreased in the elderly and bioavailability was increased.
The plasma clearance of omeprazole was 250 mL/min (about half that
of young volunteers) and its plasma half-life averaged one hour, about
twice that of young healthy volunteers. However, no dosage
adjustment is necessary in the elderly [see Clinical Pharmacology
(12.3)].
8.6
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis [see Clinical Pharmacology (12.3)].
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Reference ID: 3675793
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8.7
Renal Impairment
No dosage reduction is necessary [see Clinical Pharmacology (12.3)].
8.8
Asian Population
Consider dose reduction, particularly for maintenance of healing of
erosive esophagitis [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
Reports have been received of overdosage with omeprazole in
humans. Doses ranged up to 2400 mg (120 times the usual
recommended clinical dose). Manifestations were variable, but
included confusion, drowsiness, blurred vision, tachycardia, nausea,
vomiting, diaphoresis, flushing, headache, dry mouth, and other
adverse reactions similar to those seen in normal clinical experience
[see Adverse Reactions (6)]. Symptoms were transient, and no
serious clinical outcome has been reported when PRILOSEC was
taken alone. No specific antidote for omeprazole overdosage is
known. Omeprazole is extensively protein bound and is, therefore,
not readily dialyzable. In the event of overdosage, treatment should
be symptomatic and supportive.
As with the management of any overdose, the possibility of multiple
drug ingestion should be considered. For current information on
treatment of any drug overdose, contact a Poison Control Center at 1-
800-222-1222.
Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were
lethal to mice, rats, and dogs, respectively. Animals given these doses
showed sedation, ptosis, tremors, convulsions, and decreased activity,
body temperature, and respiratory rate and increased depth of
respiration.
11
DESCRIPTION
The active ingredient in PRILOSEC (omeprazole) Delayed-Release
Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-
3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a
compound that inhibits gastric acid secretion. Its empirical formula is
C17 H19 N3O3S, with a molecular weight of 345.42. The structural
formula is:
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Reference ID: 3675793
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Omeprazole is a white to off-white crystalline powder that melts with
decomposition at about 155°C. It is a weak base, freely soluble in
ethanol and methanol, and slightly soluble in acetone and isopropanol
and very slightly soluble in water. The stability of omeprazole is a
function of pH; it is rapidly degraded in acid media, but has
acceptable stability under alkaline conditions.
The active ingredient in PRILOSEC (omeprazole magnesium) for
Delayed-Release Oral Suspension, is 5-Methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium
salt (2:1)
Omeprazole magnesium is a white to off white powder with a melting
point with degradation at 200°C. The salt is slightly soluble (0.25
mg/mL) in water at 25°C, and it is soluble in methanol. The half-life
is highly pH dependent.
The empirical formula for omeprazole magnesium is
(C17 H18 N3O3S)2 Mg, the molecular weight is 713.12 and the
structural formula is:
PRILOSEC is supplied as delayed-release capsules for oral
administration. Each delayed-release capsule contains either 10 mg,
20 mg or 40 mg of omeprazole in the form of enteric-coated granules
with the following inactive ingredients: cellulose, disodium hydrogen
phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate and other ingredients. The capsule shells have
the following inactive ingredients: gelatin-NF, FD&C Blue #1,
FD&C Red #40, D&C Red #28, titanium dioxide, synthetic black iron
oxide, isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7
Calcium Lake, and, in addition, the 10 mg and 40 mg capsule shells
also contain D&C Yellow #10.
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Reference ID: 3675793
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Each packet of PRILOSEC For Delayed-Release Oral Suspension
contains either 2.8 mg or 11.2 mg of omeprazole magnesium
(equivalent to 2.5 mg or 10 mg of omeprazole), in the form of enteric-
coated granules with the following inactive ingredients: glyceryl
monostearate, hydroxypropyl cellulose, hypromellose, magnesium
stearate, methacrylic acid copolymer C, polysorbate, sugar spheres,
talc, and triethyl citrate, and also inactive granules. The inactive
granules are composed of the following ingredients: citric acid,
crospovidone, dextrose, hydroxypropyl cellulose, iron oxide and
xantham gum. The omeprazole granules and inactive granules are
constituted with water to form a suspension and are given by oral,
nasogastric or direct gastric administration.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Omeprazole belongs to a class of antisecretory compounds, the
substituted benzimidazoles, that suppress gastric acid secretion by
specific inhibition of the H+/K+ ATPase enzyme system at the
secretory surface of the gastric parietal cell. Because this enzyme
system is regarded as the acid (proton) pump within the gastric
mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect
is dose-related and leads to inhibition of both basal and stimulated
acid secretion irrespective of the stimulus. Animal studies indicate
that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
12.2 Pharmacodynamics
Antisecretory Activity
After oral administration, the onset of the antisecretory effect of
omeprazole occurs within one hour, with the maximum effect
occurring within two hours. Inhibition of secretion is about 50% of
maximum at 24 hours and the duration of inhibition lasts up to 72
hours. The antisecretory effect thus lasts far longer than would be
expected from the very short (less than one hour) plasma half-life,
apparently due to prolonged binding to the parietal H+/K+ ATPase
enzyme. When the drug is discontinued, secretory activity returns
gradually, over 3 to 5 days. The inhibitory effect of omeprazole on
acid secretion increases with repeated once-daily dosing, reaching a
plateau after four days.
Results from numerous studies of the antisecretory effect of multiple
doses of 20 mg and 40 mg of omeprazole in normal volunteers and
patients are shown below. The “max” value represents determinations
at a time of maximum effect (2-6 hours after dosing), while “min”
values are those 24 hours after the last dose of omeprazole.
Table 1
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Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole
After Multiple Daily Dosing
Omeprazole
Omeprazole
Parameter
20 mg
40 mg
% Decrease in Basal Acid
Output
Max
78*
Min
58-80
Max
94*
Min
80-93
% Decrease in Peak Acid
Output
79*
50-59
88*
62-68
% Decrease in 24-hr.
Intragastric Acidity
80-97
92-94
*Single Studies
Single daily oral doses of omeprazole ranging from a dose of 10 mg
to 40 mg have produced 100% inhibition of 24-hour intragastric
acidity in some patients.
Serum Gastrin Effects
In studies involving more than 200 patients, serum gastrin levels
increased during the first 1 to 2 weeks of once-daily administration of
therapeutic doses of omeprazole in parallel with inhibition of acid
secretion. No further increase in serum gastrin occurred with
continued treatment. In comparison with histamine H2-receptor
antagonists, the median increases produced by 20 mg doses of
omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase).
Gastrin values returned to pretreatment levels, usually within 1 to 2
weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and
increased serum Chromogranin A (CgA) levels. The increased CgA
levels may cause false positive results in diagnostic investigations for
neuroendocrine tumors. Healthcare providers should temporarily stop
omeprazole treatment at least 14 days before assessing CgA levels
and consider repeating the test if initial CgA levels are high.
Enterochromaffin-like (ECL) Cell Effects
Human gastric biopsy specimens have been obtained from more than
3000 patients (both children and adults) treated with omeprazole in
long-term clinical trials. The incidence of ECL cell hyperplasia in
these studies increased with time; however, no case of ECL cell
carcinoids, dysplasia, or neoplasia has been found in these patients
[see Clinical Pharmacology (12)]. However, these studies are of
insufficient duration and size to rule out the possible influence of
long-term administration of omeprazole on the development of any
premalignant or malignant conditions.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and
respiratory systems have not been found to date. Omeprazole, given
in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid
function, carbohydrate metabolism, or circulating levels of
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parathyroid hormone, cortisol, estradiol, testosterone, prolactin,
cholecystokinin or secretin.
No effect on gastric emptying of the solid and liquid components of a
test meal was demonstrated after a single dose of omeprazole 90 mg.
In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had
no effect on intrinsic factor secretion. No systematic dose-dependent
effect has been observed on basal or stimulated pepsin output in
humans.
However, when intragastric pH is maintained at 4.0 or above, basal
pepsin output is low, and pepsin activity is decreased.
As do other agents that elevate intragastric pH, omeprazole
administered for 14 days in healthy subjects produced a significant
increase in the intragastric concentrations of viable bacteria. The
pattern of the bacterial species was unchanged from that commonly
found in saliva. All changes resolved within three days of stopping
treatment.
The course of Barrett’s esophagus in 106 patients was evaluated in a
U.S. double-blind controlled study of PRILOSEC 40 mg twice daily
for 12 months followed by 20 mg twice daily for 12 months or
ranitidine 300 mg twice daily for 24 months. No clinically significant
impact on Barrett’s mucosa by antisecretory therapy was observed.
Although neosquamous epithelium developed during antisecretory
therapy, complete elimination of Barrett’s mucosa was not achieved.
No significant difference was observed between treatment groups in
development of dysplasia in Barrett’s mucosa and no patient
developed esophageal carcinoma during treatment. No significant
differences between treatment groups were observed in development
of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal
metaplasia, or colon polyps exceeding 3 mm in diameter [see Clinical
Pharmacology (12)].
12.3 Pharmacokinetics
Absorption
PRILOSEC Delayed-Release Capsules contain an enteric-coated
granule formulation of omeprazole (because omeprazole is acid-
labile), so that absorption of omeprazole begins only after the
granules leave the stomach. Absorption is rapid, with peak plasma
levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma
concentrations of omeprazole and AUC are approximately
proportional to doses up to 40 mg, but because of a saturable first-
pass effect, a greater than linear response in peak plasma
concentration and AUC occurs with doses greater than 40 mg.
Absolute bioavailability (compared with intravenous administration)
is about 30-40% at doses of 20-40 mg, due in large part to
presystemic metabolism. In healthy subjects the plasma half-life is 0.5
to 1 hour, and the total body clearance is 500-600 mL/min.
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Reference ID: 3675793
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Based on a relative bioavailability study, the AUC and Cmax of
PRILOSEC (omeprazole magnesium) for Delayed-Release Oral
Suspension were 87% and 88% of those for PRILOSEC Delayed-
Release Capsules, respectively.
The bioavailability of omeprazole increases slightly upon repeated
administration of PRILOSEC Delayed-Release Capsules.
PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when
administered with and without applesauce. However, PRILOSEC
Delayed-Release Capsule 20 mg was not bioequivalent when
administered with and without applesauce. When administered with
applesauce, a mean 25% reduction in Cmax was observed without a
significant change in AUC for PRILOSEC Delayed-Release Capsule
20 mg. The clinical relevance of this finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450
(CYP) enzyme system.
Excretion
Following single dose oral administration of a buffered solution of
omeprazole, little if any unchanged drug was excreted in urine. The
majority of the dose (about 77%) was eliminated in urine as at least
six metabolites. Two were identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was
recoverable in feces. This implies a significant biliary excretion of the
metabolites of omeprazole. Three metabolites have been identified in
plasma - the sulfide and sulfone derivatives of omeprazole, and
hydroxyomeprazole. These metabolites have very little or no
antisecretory activity.
Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with
clarithromycin 500 mg every 8 hours to healthy adult male subjects.
The steady state plasma concentrations of omeprazole were increased
(Cmax , AUC0-24 , and T1/2 increases of 30%, 89% and 34%
respectively) by the concomitant administration of clarithromycin.
The observed increases in omeprazole plasma concentration were
associated with the following pharmacological effects. The mean 24-
hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin
were increased by the concomitant administration of omeprazole. For
clarithromycin, the mean C max was 10% greater, the mean C min was
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27% greater, and the mean AUC0-8 was 15% greater when
clarithromycin was administered with omeprazole than when
clarithromycin was administered alone. Similar results were seen for
14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the
mean C min was 57% greater, and the mean AUC0-8 was 45% greater.
Clarithromycin concentrations in the gastric tissue and mucus were
also increased by concomitant administration of omeprazole.
Table 2
Clarithromycin Tissue Concentrations
2 hours after Dose
1
Clarithromycin +
Tissue
Clarithromycin
Omeprazole
Antrum
10.48 ± 2.01 (n = 5)
19.96 ± 4.71 (n = 5)
Fundus
20.81 ± 7.64 (n = 5)
24.25 ± 6.37 (n = 5)
Mucus
4.15 ± 7.74 (n = 4)
39.29 ± 32.79 (n = 4)
1Mean ± SD (µg/g)
Concomitant Use with Clopidogrel
In a crossover clinical study, 72 healthy subjects were administered
clopidogrel (300 mg loading dose followed by 75 mg per day) alone
and with omeprazole (80 mg at the same time as clopidogrel) for 5
days. The exposure to the active metabolite of clopidogrel was
decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and
omeprazole were administered together.
Results from another crossover study in healthy subjects showed a
similar pharmacokinetic interaction between clopidogrel (300 mg
loading dose/75 mg daily maintenance dose) and omeprazole 80 mg
daily when co-administered for 30 days. Exposure to the active
metabolite of clopidogrel was reduced by 41% to 46% over this time
period.
In another study, 72 healthy subjects were given the same doses of
clopidogrel and 80 mg omeprazole but the drugs were administered
12 hours apart; the results were similar, indicating that administering
clopidogrel and omeprazole at different times does not prevent their
interaction.
Concomitant Use with Mycophenolate Mofetil
Administration of omeprazole 20 mg twice daily for 4 days and a
single 1000 mg dose of MMF approximately one hour after the last
dose of omeprazole to 12 healthy subjects in a cross-over study
resulted in a 52% reduction in the Cmax and 23% reduction in the
AUC of MPA.
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the
elderly, and bioavailability was increased. Omeprazole was 76%
25
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bioavailable when a single 40 mg oral dose of omeprazole (buffered
solution) was administered to healthy elderly volunteers, versus 58%
in young volunteers given the same dose. Nearly 70% of the dose was
recovered in urine as metabolites of omeprazole and no unchanged
drug was detected. The plasma clearance of omeprazole was 250
mL/min (about half that of young volunteers) and its plasma half-life
averaged one hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in
pediatric patients 2 to 16 years of age:
Table 3
Pharmacokinetic Parameters of Omeprazole Following Single
and Repeated Oral Administration in Pediatric Populations
Compared with Adults
Single or
Children†
Children†
Adults‡
Repeated
< 20 kg
> 20 kg
(mean
Oral Dosing
2-5 years
6-16
76 kg)
/Parameter
10 mg
years
23-29
20 mg
years
(n=12)
Single Dosing
Cmax *
288
495
668
(ng/mL)
(n=10)
(n=49)
AUC*
511
1140
1220
(ng h/mL)
(n=7)
(n=32)
Repeated Dosing
Cmax *
539
851
1458
(ng/mL)
(n=4)
(n=32)
AUC*
1179
2276
3352
(ng h/mL)
(n=2)
(n=23)
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
†Data from single and repeated dose studies
‡Data from a single and repeated dose study
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children
(2 to 5 years of age) have lower AUCs than children 6 to 16 years of
age or adults; AUCs of the latter two groups did not differ [see
Dosage and Administration (2)].
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased
to approximately 100% compared with an I.V. dose, reflecting
decreased first-pass effect, and the plasma half-life of the drug
increased to nearly 3 hours compared with the half-life in normals of
0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a
value of 500-600 mL/min in normal subjects. Dose reduction,
26
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particularly where maintenance of healing of erosive esophagitis is
indicated, for the hepatically impaired should be considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance
ranged between 10 and 62 mL/min/1.73 m2, the disposition of
omeprazole was very similar to that in healthy volunteers, although
there was a slight increase in bioavailability. Because urinary
excretion is a primary route of excretion of omeprazole metabolites,
their elimination slowed in proportion to the decreased creatinine
clearance. No dose reduction is necessary in patients with renal
impairment.
Asian Population
In pharmacokinetic studies of single 20 mg omeprazole doses, an
increase in AUC of approximately four-fold was noted in Asian
subjects compared with Caucasians. Dose reduction, particularly
where maintenance of healing of erosive esophagitis is indicated, for
Asian subjects should be considered.
12.4 Microbiology
Omeprazole and clarithromycin dual therapy and omeprazole,
clarithromycin and amoxicillin triple therapy have been shown to be
active against most strains of Helicobacter pylori in vitro and in
clinical infections as described in the Indications and Usage section
(1.1).
Helicobacter
Helicobacter pylori- Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the
omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3%
(41/439) in omeprazole/clarithromycin/amoxicillin triple therapy
studies (1, 2, and 3).
Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were
found in 99.3% (436/439) of the patients in the
omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2,
and 3). Amoxicillin pretreatment minimum inhibitory concentrations
(MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of
whom were in the clarithromycin and amoxicillin study arm. One
patient had an unconfirmed pretreatment amoxicillin minimum
inhibitory concentration (MIC) of > 256 µg/mL by Etest® .
Table 4
Clarithromycin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
27
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Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a
Clarithromycin Pretreatment Results
Clarithromycin Post-treatment Results
H. pylori negative –
eradicated
H. pylori positive – not eradicated
Post-treatment susceptibility results
S b
I b
R b
No MIC
Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed
by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5)
Susceptible b
108
72
1
26
9
Intermediate b
1
1
Resistant b
4
4
Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice
daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies
1, 2)
Susceptible b
171
153
7
3
8
Intermediateb
Resistant b
14
4
1
6
3
aIncludes only patients with pretreatment clarithromycin susceptibility test results
bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC 0.5 – 1.0 µg/mL, Resistant (R) MIC ≥ 2
µg/mL
Patients not eradicated of H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy or
omeprazole/clarithromycin dual therapy will likely have
clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with
clarithromycin resistant H. pylori should not be treated with any of
the following: omeprazole/clarithromycin dual therapy,
omeprazole/clarithromycin/amoxicillin triple therapy, or other
regimens which include clarithromycin as the sole antimicrobial
agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
In the triple therapy clinical trials, 84.9% (157/185) of the patients in
the omeprazole/clarithromycin/amoxicillin treatment group who had
pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were
eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment
susceptibility test results and 17 had post-treatment H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed
triple therapy also had post-treatment H. pylori isolates with
clarithromycin resistant MICs.
Susceptibility Test for Helicobacter pylori
For susceptibility testing information about Helicobacter pylori, see
Microbiology section in prescribing information for clarithromycin
and amoxicillin.
Effects on Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including proton pump
inhibitors, increases gastric counts of bacteria normally present in the
gastrointestinal tract. Treatment with proton pump inhibitors may
lead to slightly increased risk of gastrointestinal infections such as
28
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Salmonella and Campylobacter and, in hospitalized patients, possibly
also Clostridium difficile.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily
doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.4 to 34
times a human dose of 40 mg/day, as expressed on a body surface
area basis) produced gastric ECL cell carcinoids in a dose-related
manner in both male and female rats; the incidence of this effect was
markedly higher in female rats, which had higher blood levels of
omeprazole. Gastric carcinoids seldom occur in the untreated rat. In
addition, ECL cell hyperplasia was present in all treated groups of
both sexes. In one of these studies, female rats were treated with 13.8
mg omeprazole/kg/day (about 3.4 times a human dose of 40 mg/day,
based on body surface area) for one year, and then followed for an
additional year without the drug. No carcinoids were seen in these
rats. An increased incidence of treatment-related ECL cell hyperplasia
was observed at the end of one year (94% treated vs 10% controls).
By the second year the difference between treated and control rats
was much smaller (46% vs 26%) but still showed more hyperplasia in
the treated group. Gastric adenocarcinoma was seen in one rat (2%).
No similar tumor was seen in male or female rats treated for two
years. For this strain of rat no similar tumor has been noted
historically, but a finding involving only one tumor is difficult to
interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain
astrocytomas were found in a small number of males that received
omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to
3.9 times the human dose of 40 mg/day, based on a body surface area
basis). No astrocytomas were observed in female rats in this study. In
a 2-year carcinogenicity study in Sprague-Dawley rats, no
astrocytomas were found in males or females at the high dose of
140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a
body surface area basis). A 78-week mouse carcinogenicity study of
omeprazole did not show increased tumor occurrence, but the study
was not conclusive. A 26-week p53 (+/-) transgenic mouse
carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an in vitro human
lymphocyte chromosomal aberration assay, in one of two in vivo
mouse micronucleus tests, and in an in vivo bone marrow cell
chromosomal aberration assay. Omeprazole was negative in the in
vitro Ames test, an in vitro mouse lymphoma cell forward mutation
assay, and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times
an oral human dose of 40 mg on a body surface area basis) was found
to have no effect on fertility and reproductive performance.
29
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In 24-month carcinogenicity studies in rats, a dose-related significant
increase in gastric carcinoid tumors and ECL cell hyperplasia was
observed in both male and female animals [see Warnings and
Precautions (5)]. Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other proton
pump inhibitors or high doses of H2-receptor antagonists.
13.2 Animal Toxicology and/or Pharmacology
Reproduction Studies
Reproductive Toxicology Studies
Reproductive studies conducted with omeprazole in rats at oral doses
up to 138 mg/kg/day (about 34 times the human dose of 40 mg/day on
a body surface area basis) and in rabbits at doses up to 69 mg/kg/day
(about 34 times the human dose on a body surface area basis) did not
disclose any evidence for a teratogenic potential of omeprazole. In
rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about
3.4 to 34 times the human dose of 40 mg/day on a body surface area
basis) produced dose-related increases in embryo-lethality, fetal
resorptions, and pregnancy disruptions. In rats, dose-related
embryo/fetal toxicity and postnatal developmental toxicity were
observed in offspring resulting from parents treated with omeprazole
at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times the human dose of
40 mg/day on a body surface area basis) [see Pregnancy, Animal
Data (8.1)].
Juvenile Animal Study
A 28-day toxicity study with a 14-day recovery phase was conducted
in juvenile rats with esomeprazole magnesium at doses of 70 to 280
mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg
on a body surface area basis). An increase in the number of deaths at
the high dose of 280 mg/kg/day was observed when juvenile rats were
administered esomeprazole magnesium from postnatal day 7 through
postnatal day 35. In addition, doses equal to or greater than 140
mg/kg/day (about 34 times a daily oral human dose of 40 mg on a
body surface area basis), produced treatment-related decreases in
body weight (approximately 14%) and body weight gain, decreases in
femur weight and femur length, and affected overall growth.
Comparable findings described above have also been observed in this
study with another esomeprazole salt, esomeprazole strontium, at
equimolar doses of esomeprazole.
14
CLINICAL STUDIES
14.1 Duodenal Ulcer Disease
Active Duodenal Ulcer— In a multicenter, double-blind, placebo-
controlled study of 147 patients with endoscopically documented
duodenal ulcer, the percentage of patients healed (per protocol) at 2
and 4 weeks was significantly higher with PRILOSEC 20 mg once
daily than with placebo (p ≤ 0.01).
30
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Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Placebo
20 mg a.m.
a.m.
Week 2
(n = 99)
* 41
(n = 48)
13
Week 4
* 75
27
*(p < 0.01)
Complete daytime and nighttime pain relief occurred significantly
faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in
patients treated with placebo. At the end of the study, significantly
more patients who had received PRILOSEC had complete relief of
daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).
In a multicenter, double-blind study of 293 patients with
endoscopically documented duodenal ulcer, the percentage of patients
healed (per protocol) at 4 weeks was significantly higher with
PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p <
0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg a.m.
150 mg twice daily
(n = 145)
(n = 148)
Week 2
42
34
Week 4
*82
63
*(p < 0.01)
Healing occurred significantly faster in patients treated with
PRILOSEC than in those treated with ranitidine 150 mg b.i.d. (p <
0.01).
In a foreign multinational randomized, double-blind study of 105
patients with endoscopically documented duodenal ulcer, 20 mg and
40 mg of PRILOSEC were compared with 150 mg b.i.d. of ranitidine
at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were
statistically superior (per protocol) to ranitidine, but 40 mg was not
superior to 20 mg of PRILOSEC, and at 8 weeks there was no
significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC
Ranitidine
20 mg
40 mg
150 mg twice
(n = 34)
(n = 36)
daily
(n = 35)
Week 2
*83
*83
53
Week 4
Week 8
*97
100
*100
100
82
94
*(p < 0.01)
31
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H. pylori Eradication in Patients with Duodenal Ulcer
Disease
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)— Three
U.S., randomized, double-blind clinical studies in patients with H.
pylori infection and duodenal ulcer disease (n = 558) compared
PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin
plus amoxicillin. Two studies (1 and 2) were conducted in patients
with an active duodenal ulcer, and the other study (3) was conducted
in patients with a history of a duodenal ulcer in the past 5 years but
without an ulcer present at the time of enrollment. The dose regimen
in the studies was PRILOSEC 20 mg twice daily plus clarithromycin
500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or
clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for
10 days. In studies 1 and 2, patients who took the omeprazole
regimen also received an additional 18 days of PRILOSEC 20 mg
once daily. Endpoints studied were eradication of H. pylori and
duodenal ulcer healing (studies 1 and 2 only). H. pylori status was
determined by CLOtest®, histology and culture in all three studies.
For a given patient, H. pylori was considered eradicated if at least two
of these tests were negative, and none was positive.
The combination of omeprazole plus clarithromycin plus amoxicillin
was effective in eradicating H. pylori.
Table 5
Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
% of Patients Cured [95% Confidence Interval]
Study 1
PRILOSEC +clarithromycin
+amoxicillin
Per-Protocol †
Intent-to-Treat ‡
*77 [64, 86]
(n = 64)
*69 [57, 79]
(n = 80)
Clarithromycin +amoxicillin
Per-Protocol †
Intent-to-Treat ‡
43 [31, 56]
(n = 67)
37 [27, 48]
(n = 84)
Study 2
*78 [67, 88]
(n = 65)
*73 [61, 82]
(n = 77)
41 [29, 54]
(n = 68)
36 [26, 47]
(n = 83)
Study 3
*90 [80, 96]
(n = 69)
*83 [74, 91]
(n = 84)
33 [24, 44]
(n = 93)
32 [23, 42]
(n = 99)
† Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer
within 5 years, study 3) and H. pylori infection at baseline defined as
at least two of three positive endoscopic tests from CLOtest ,
histology, and/or culture. Patients were included in the analysis if
they completed the study. Additionally, if patients dropped out of
the study due to an adverse event related to the study drug, they were
included in the analysis as failures of therapy. The impact of
eradication on ulcer recurrence has not been assessed in patients with
a past history of ulcer.
‡ Patients were included in the analysis if they had documented
H. pylori infection at baseline and had confirmed duodenal ulcer
disease. All dropouts were included as failures of therapy.
* (p < 0.05) versus clarithromycin plus amoxicillin.
32
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Dual Therapy (PRILOSEC/clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7)
evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg
three times daily for 14 days, followed by PRILOSEC 20 mg once
daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study
6) for an additional 14 days in patients with active duodenal ulcer
associated with H. pylori. Studies 4 and 5 were conducted in the U.S.
and Canada and enrolled 242 and 256 patients, respectively. H. pylori
infection and duodenal ulcer were confirmed in 219 patients in Study
4 and 228 patients in Study 5. These studies compared the
combination regimen to PRILOSEC and clarithromycin
monotherapies. Studies 6 and 7 were conducted in Europe and
enrolled 154 and 215 patients, respectively. H. pylori infection and
duodenal ulcer were confirmed in 148 patients in Study 6 and 208
patients in Study 7. These studies compared the combination regimen
with omeprazole monotherapy. The results for the efficacy analyses
for these studies are described below. H. pylori eradication was
defined as no positive test (culture or histology) at 4 weeks following
the end of treatment, and two negative tests were required to be
considered eradicated of H. pylori. In the per-protocol analysis, the
following patients were excluded: dropouts, patients with missing H.
pylori tests post-treatment, and patients that were not assessed for H.
pylori eradication because they were found to have an ulcer at the end
of treatment.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori.
Table 6
H. pylori Eradication Rates (Per-Protocol Analysis
at 4 to 6 Weeks)
% of Patients Cured [95% Confidence Interval]
PRILOSEC +
Clarithromycin
PRILOSEC
Clarithromycin
U.S. Studies
Study 4
74 [60, 85] †‡
(n = 53)
0 [0, 7]
(n = 54)
31 [18, 47]
(n = 42)
Study 5
64 [51, 76] †‡
(n = 61)
0 [0, 6]
(n = 59)
39 [24, 55]
(n = 44)
Non U.S. Studies
Study 6
83 [71, 92] ‡
(n = 60)
1 [0, 7]
(n = 74)
N/A
Study 7
74 [64, 83] ‡
(n = 86)
1 [0, 6]
(n = 90)
N/A
†Statistically significantly higher than clarithromycin
monotherapy (p < 0.05)
‡Statistically significantly higher than omeprazole
monotherapy (p < 0.05)
Ulcer healing was not significantly different when clarithromycin was
added to omeprazole therapy compared with omeprazole therapy
alone.
The combination of omeprazole and clarithromycin was effective in
eradicating H. pylori and reduced duodenal ulcer recurrence.
33
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Table 7
Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status
% of Patients with Ulcer Recurrence
H. pylori eradicated#
H. pylori not eradicated#
U.S. Studies †
6 months post-treatment
Study 4
*35
60
(n = 49)
(n = 88)
Study 5
*8
60
(n = 53)
(n = 106)
Non U.S. Studies ‡
6 months post-treatment
Study 6
*5
46
(n = 43)
(n = 78)
Study 7
*6
43
(n = 53)
(n = 107)
12 months post-treatment
Study 6
*5
68
(n = 39)
(n = 71)
#H. pylori eradication status assessed at same time point as ulcer recurrence
†Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment
arms
‡Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
*(p < 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori
eradicated
14.2 Gastric Ulcer
In a U.S. multicenter, double-blind, study of omeprazole 40 mg once
daily, 20 mg once daily, and placebo in 520 patients with
endoscopically diagnosed gastric ulcer, the following results were
obtained.
Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC
PRILOSEC
20 mg once daily
40 mg once daily
Placebo
(n = 202)
(n = 214)
(n = 104)
Week 4
47.5**
55.6**
30.8
Week 8
48.1
74.8**
82.7**,+
**(p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
+(p < 0.05) PRILOSEC 40 mg versus 20 mg
For the stratified groups of patients with ulcer size less than or equal
to 1 cm, no difference in healing rates between 40 mg and 20 mg was
detected at either 4 or 8 weeks. For patients with ulcer size greater
than 1 cm, 40 mg was significantly more effective than 20 mg at 8
weeks.
In a foreign, multinational, double-blind study of 602 patients with
endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily,
20 mg once daily, and ranitidine 150 mg twice a day were evaluated.
34
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Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
Week 4
Week 8
PRILOSEC
20 mg once daily
(n = 200)
63.5
81.5
PRILOSEC
40 mg once daily
(n = 187)
78.1**,++
91.4**,++
Ranitidine
150 mg twice daily
(n = 199)
56.3
78.4
** (p < 0.01) PRILOSEC 40 mg versus ranitidine
++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
14.3 Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo-controlled study was conducted in Scandinavia to compare
the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4
weeks in the treatment of heartburn and other symptoms in GERD
patients without erosive esophagitis. Results are shown below.
% Successful Symptomatic Outcomea
PRILOSEC
PRILOSEC
Placebo
20 mg a.m.
10 mg a.m.
a.m.
All patients
46*,†
31†
13
(n = 105)
(n = 205)
(n = 199)
Patients with
14
56*,†
36†
confirmed GERD
(n = 59)
(n = 115)
(n = 109)
aDefined as complete resolution of heartburn
*(p < 0.005) versus 10 mg
†(p < 0.005) versus placebo
14.4 Erosive Esophagitis
In a U.S. multicenter double-blind placebo controlled study of 20 mg
or 40 mg of PRILOSEC Delayed-Release Capsules in patients with
symptoms of GERD and endoscopically diagnosed erosive
esophagitis of grade 2 or above, the percentage healing rates (per
protocol) were as follows:
20 mg PRILOSEC
40 mg PRILOSEC
Placebo
Week
(n = 83)
(n = 87)
(n = 43)
4
39**
45**
7
8
14
74**
75**
** (p < 0.01) PRILOSEC versus placebo.
In this study, the 40 mg dose was not superior to the 20 mg dose of
PRILOSEC in the percentage healing rate. Other controlled clinical
trials have also shown that PRILOSEC is effective in severe GERD.
In comparisons with histamine H2-receptor antagonists in patients
with erosive esophagitis, grade 2 or above, PRILOSEC in a dose of
20 mg was significantly more effective than the active controls.
Complete daytime and nighttime heartburn relief occurred
significantly faster (p < 0.01) in patients treated with PRILOSEC than
in those taking placebo or histamine H2- receptor antagonists.
35
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In this and five other controlled GERD studies, significantly more
patients taking 20 mg omeprazole (84%) reported complete relief of
GERD symptoms than patients receiving placebo (12%).
Long-Term Maintenance Of Healing of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled
study, two dose regimens of PRILOSEC were studied in patients with
endoscopically confirmed healed esophagitis. Results to determine
maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
PRILOSEC
PRILOSEC
20 mg 3 days
20 mg once daily
per week
Placebo
(n = 138)
(n = 137)
(n = 131)
Percent in
endoscopic
remission at
6 months
34
11
*70
∗(p < 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 20 mg 3 consecutive days per week or
placebo.
In an international multicenter double-blind study, PRILOSEC 20 mg
daily and 10 mg daily were compared with ranitidine 150 mg twice
daily in patients with endoscopically confirmed healed esophagitis.
The table below provides the results of this study for maintenance of
healing of erosive esophagitis.
Life Table Analysis
PRILOSEC
PRILOSEC
Ranitidine
20 mg once daily
10 mg once daily
150 mg twice daily
(n = 131)
(n = 133)
(n = 128)
Percent in
endoscopic
remission at
12 months
46
*77
‡58
*
(p = 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 10 mg once daily or
Ranitidine.
‡ (p = 0.03) PRILOSEC 10 mg once daily versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for
maintenance after healing 20 mg daily of PRILOSEC was effective,
while 10 mg did not demonstrate effectiveness.
14.5 Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory
conditions, such as Zollinger-Ellison (ZE) syndrome with or without
multiple endocrine adenomas, PRILOSEC Delayed-Release Capsules
significantly inhibited gastric acid secretion and controlled associated
symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg
every other day to 360 mg per day maintained basal acid secretion
below 10 mEq/hr in patients without prior gastric surgery, and below
5 mEq/hr in patients with prior gastric surgery.
36
Reference ID: 3675793
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Initial doses were titrated to the individual patient need, and
adjustments were necessary with time in some patients [see Dosage
and Administration (2)]. PRILOSEC was well tolerated at these high
dose levels for prolonged periods (> 5 years in some patients). In
most ZE patients, serum gastrin levels were not modified by
PRILOSEC. However, in some patients serum gastrin increased to
levels greater than those present prior to initiation of omeprazole
therapy. At least 11 patients with ZE syndrome on long-term
treatment with PRILOSEC developed gastric carcinoids. These
findings are believed to be a manifestation of the underlying
condition, which is known to be associated with such tumors, rather
than the result of the administration of PRILOSEC [see Adverse
Reactions (6)].
14.6 Pediatric GERD
Symptomatic GERD
The effectiveness of PRILOSEC for the treatment of nonerosive
GERD in pediatric patients 1 to 16 years of age is based in part on
data obtained from 125 pediatric patients in two uncontrolled Phase
III studies [see Use in Specific Populations (8.4)].
The first study enrolled 12 pediatric patients 1 to 2 years of age with a
history of clinically diagnosed GERD. Patients were administered a
single dose of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8
weeks as an open capsule in 8.4% sodium bicarbonate solution.
Seventy-five percent (9/12) of the patients had vomiting/regurgitation
episodes decreased from baseline by at least 50%.
The second study enrolled 113 pediatric patients 2 to 16 years of age
with a history of symptoms suggestive of nonerosive GERD. Patients
were administered a single dose of omeprazole (10 mg or 20 mg,
based on body weight) for 4 weeks either as an intact capsule or as an
open capsule in applesauce. Successful response was defined as no
moderate or severe episodes of either pain-related symptoms or
vomiting/regurgitation during the last 4 days of treatment. Results
showed success rates of 60% (9/15; 10 mg omeprazole) and 59%
(58/98; 20 mg omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive
esophagitis in pediatric patients 1 to 16 years of age required doses
that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were
initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7
mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than
6% of a 24-hour study). After titration, patients remained on
treatment for 3 months. Forty-four percent of the patients were healed
on a dose of 0.7 mg/kg body weight; most of the remaining patients
were healed with 1.4 mg/kg after an additional 3 months’ treatment.
Erosive esophagitis was healed in 51 of 57 (90%) children who
completed the first course of treatment in the healing phase of the
37
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
study. In addition, after 3 months of treatment, 33% of the children
had no overall symptoms, 57% had mild reflux symptoms, and 40%
had less frequent regurgitation/vomiting.
Maintenance of Healing of Erosive Esophagitis
In an uncontrolled, open-label study of maintenance of healing of
erosive esophagitis in 46 pediatric patients, 54% of patients required
half the healing dose. The remaining patients increased the healing
dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire
maintenance period, or returned to half the dose before completion.
Of the 46 patients who entered the maintenance phase, 19 (41%) had
no relapse. In addition, maintenance therapy in erosive esophagitis
patients resulted in 63% of patients having no overall symptoms.
15
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods
for Dilution Antimicrobial Susceptibility Tests for Bacteria That
Grow Aerobically—Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January
2000.
16
HOW SUPPLIED/STORAGE AND HANDLING
PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 606 on cap and
PRILOSEC 10 on the body. They are supplied as follows:
NDC 0186-0606-31 unit of use bottles of 30
PRILOSEC Delayed-Release Capsules, 20 mg, are opaque, hard
gelatin, amethyst colored capsules, coded 742 on cap and PRILOSEC
20 on body. They are supplied as follows:
NDC 0186-0742-31 unit of use bottles of 30
NDC 0186-0742-82 bottles of 1000
PRILOSEC Delayed-Release Capsules, 40 mg, are opaque, hard
gelatin, apricot and amethyst colored capsules, coded 743 on cap and
PRILOSEC 40 on the body. They are supplied as follows:
NDC 0186-0743-31 unit of use bottles of 30
NDC 0186-0743-68 bottles of 100
PRILOSEC For Delayed-Release Oral Suspension, 2.5 mg or 10 mg,
is supplied as a unit dose packet containing a fine yellow powder,
consisting of white to brownish omeprazole granules and pale yellow
inactive granules. PRILOSEC unit dose packets are supplied as
follows:
38
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 0186-0625-01 unit dose packages of 30: 2.5 mg packets
NDC 0186-0610-01 unit dose packages of 30: 10 mg packets
Storage
Store PRILOSEC Delayed-Release Capsules in a tight container
protected from light and moisture. Store between 15°C and 30°C
(59°F and 86°F).
Store PRILOSEC For Delayed-Release Oral Suspension at 25°C
(77°F); excursions permitted to 15 – 30°C (59 – 86°F). [See USP
Controlled Room Temperature.]
17
PATIENT COUNSELING INFORMATION
“See FDA-Approved Medication Guide”
PRILOSEC should be taken before eating. Patients should be
informed that the PRILOSEC Delayed-Release Capsule should be
swallowed whole.
For patients who have difficulty swallowing capsules, the contents of
a PRILOSEC Delayed-Release Capsule can be added to applesauce.
One tablespoon of applesauce should be added to an empty bowl and
the capsule should be opened. All of the pellets inside the capsule
should be carefully emptied on the applesauce. The pellets should be
mixed with the applesauce and then swallowed immediately with a
glass of cool water to ensure complete swallowing of the pellets. The
applesauce used should not be hot and should be soft enough to be
swallowed without chewing. The pellets should not be chewed or
crushed. The pellets/applesauce mixture should not be stored for
future use.
PRILOSEC For Delayed-Release Oral Suspension should be
administered as follows:
• Empty the contents of a 2.5 mg packet into a container
containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container
containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water,
stir and drink immediately.
For patients with a nasogastric or gastric tube in place:
39
Reference ID: 3675793
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Add 5 mL of water to a catheter tipped syringe and
then add the contents of a 2.5 mg packet (or 15 mL of
water for the 10 mg packet). It is important to only use
a catheter tipped syringe when administering
PRILOSEC through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3
minutes to thicken.
• Shake the syringe and inject through the nasogastric or
gastric tube, French size 6 or larger, into the stomach
within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the
nasogastric or gastric tube into the stomach.
Advise patients to immediately report and seek care for diarrhea that
does not improve. This may be a sign of Clostridium difficile
associated diarrhea [see Warnings and Precautions (5.5)].
Advise patients to immediately report and seek care for any
cardiovascular or neurological symptoms including palpitations,
dizziness, seizures, and tetany as these may be signs of
hypomagnesemia [see Warnings and Precautions (5.8)].
PRILOSEC is a trademark of the AstraZeneca group of companies.
Manufactured for: AstraZeneca LP, Wilmington, DE 19850
©AstraZeneca 2014
Rev.
40
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
PRILOSEC (pry-lo-sec)
(omeprazole)
delayed-release capsules
PRILOSEC (pry-lo-sec)
(omeprazole magnesium)
for delayed-release oral suspension
Read this Medication Guide before you start taking
PRILOSEC and each time you get a refill. There may be new
information. This information does not take the place of
talking with your doctor about your medical condition or
your treatment.
What is the most important information I should
know about PRILOSEC?
PRILOSEC may help your acid-related symptoms, but
you could still have serious stomach problems. Talk
with your doctor.
PRILOSEC can cause serious side effects, including:
• Diarrhea. PRILOSEC may increase your risk of
getting severe diarrhea. This diarrhea may be caused
by an infection (Clostridium difficile) in your
intestines.
Call your doctor right away if you have watery stool,
stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily
doses of proton pump inhibitor medicines for a long
period of time (a year or longer) may have an
increased risk of fractures of the hip, wrist, or spine.
You should take PRILOSEC exactly as prescribed, at
the lowest dose possible for your treatment and for
the shortest time needed. Talk to your doctor about
your risk of bone fracture if you take PRILOSEC.
PRILOSEC can have other serious side effects. See “What
are the possible side effects of PRILOSEC?”
What is PRILOSEC?
PRILOSEC is a prescription medicine called a proton pump
inhibitor (PPI). PRILOSEC reduces the amount of acid in
your stomach.
PRILOSEC is used in adults:
41
Reference ID: 3675793
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• for up to 8 weeks for the healing of duodenal ulcers.
The duodenal area is the area where food passes
when it leaves the stomach.
• with certain antibiotics to treat an infection caused by
bacteria called H. pylori. Sometimes H. pylori
bacteria can cause duodenal ulcers. The infection
needs to be treated to prevent the ulcers from coming
back.
• for up to 8 weeks for healing stomach ulcers.
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
GERD happens when acid in your stomach backs up
into the tube (esophagus) that connects your mouth
to your stomach. This may cause a burning feeling in
your chest or throat, sour taste, or burping.
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE). If needed, your doctor may decide to prescribe
another 4 weeks of PRILOSEC.
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used for
longer than 12 months (1 year) for this purpose.
• for the long-term treatment of conditions where your
stomach makes too much acid. This includes a rare
condition called Zollinger-Ellison Syndrome.
For children 1 to 16 years of age, PRILOSEC is used:
• for up to 4 weeks to treat heartburn and other
symptoms that happen with gastroesophageal reflux
disease (GERD).
• for up to 8 weeks to heal acid-related damage to the
lining of the esophagus (called erosive esophagitis or
EE)
• to maintain healing of the esophagus. It is not known
if PRILOSEC is safe and effective when used longer
than 12 months (1 year) for this purpose.
It is not known if PRILOSEC is safe and effective for the
treatment of gastroesophageal reflux disease (GERD)
in children under 1 year of age.
Who should not take PRILOSEC?
Do not take PRILOSEC if you:
• are allergic to omeprazole or any of the ingredients in
PRILOSEC. See the end of this Medication Guide for a
complete list of ingredients in PRILOSEC.
42
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• are allergic to any other Proton Pump Inhibitor (PPI)
medicine.
What should I tell my doctor before taking PRILOSEC?
Before you take PRILOSEC, tell your doctor if you:
• have been told that you have low magnesium levels
in your blood
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is
not known if PRILOSEC will harm your unborn
baby.
• are breastfeeding or plan to breastfeed.
PRILOSEC passes into your breast milk. Talk to
your doctor about the best way to feed your baby
if you take PRILOSEC.
Tell your doctor about all of the medicines you take
including prescription and non-prescription drugs, anti
cancer drugs, vitamins and herbal supplements. PRILOSEC
may affect how other medicines work, and other medicines
may affect how PRILOSEC works.
Especially tell your doctor if you take:
• atazanavir (Reyataz)
• nelfinavir (Viracept)
• saquinavir (Fortovase)
• cilostazol (Pletal)
• ketoconazole (Nizoral)
• voriconazole (Vfend)
• an antibiotic that contains ampicillin, amoxicillin or
clarithromycin
• products that contain iron
• warfarin (Coumadin, Jantoven)
• digoxin (Lanoxin)
• tacrolimus (Prograf)
• diazepam (Valium)
• phenytoin (Dilantin)
• disulfiram (Antabuse)
• clopidogrel (Plavix)
• St. John’s Wort (Hypericum perforatum)
• rifampin (Rimactane, Rifater, Rifamate),
• erlotinib (Tarceva)
• methotrexate
• mycophenolate mofetil (Cellcept)
Ask your doctor or pharmacist for a list of these
medicines if you are not sure.
Know the medicines that you take. Keep a list of them to
show your doctor and pharmacist when you get a new
medicine.
43
Reference ID: 3675793
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For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take PRILOSEC?
• Take PRILOSEC exactly as prescribed by your doctor.
• Do not change your dose or stop PRILOSEC without
talking to your doctor.
• Take PRILOSEC at least 1 hour before a meal.
• Swallow PRILOSEC capsules whole. Do not chew or
crush PRILOSEC Capsules.
• If you have trouble swallowing PRILOSEC Capsules,
you may take as follows:
o Place 1 tablespoon of applesauce into a clean
bowl.
o Carefully open the capsule and empty the
contents (pellets) onto the applesauce. Mix the
pellets with the applesauce.
o Swallow the applesauce and pellet mixture
right away with a glass of cool water. Do not
chew or crush the pellets. Do not store the
applesauce and pellet mixture for later use.
• If you forget to take a dose of PRILOSEC, take it as
soon as you remember. If it is almost time for your
next dose, do not take the missed dose. Take the
next dose on time. Do not take a double dose to
make up for a missed dose.
• If you take too much PRILOSEC, tell your doctor right
away.
• See the “Instructions for Use” at the end of this
Medication Guide for instructions on how to take
PRILOSEC For Delayed-Release Oral Suspension, and
how to mix and give PRILOSEC For Delayed-Release
Oral Suspension, through a nasogastric tube or
gastric tube.
What are the possible side effects of PRILOSEC?
PRILOSEC can cause serious side effects, including:
• See “What is the most important information I
should know about PRILOSEC?”
• Chronic (lasting a long time) inflammation of
the stomach lining (Atrophic Gastritis). Using
PRILOSEC for a long period of time may increase the
risk of inflammation to your stomach lining. You may
or may not have symptoms. Tell your doctor if you
have stomach pain, nausea, vomiting, or weight loss.
• Vitamin B-12 deficiency. PRILOSEC reduces the
amount of acid in your stomach. Stomach acid is
needed to absorb vitamin B-12 properly. Talk with
your doctor about the possibility of vitamin B-12
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Reference ID: 3675793
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deficiency if you have been on PRILOSEC for a long
time (more than 3 years).
● Low magnesium levels in your body. Low
magnesium can happen in some people who take a
proton pump inhibitor medicine for at least 3 months.
If low magnesium levels happen, it is usually after a
year of treatment.
You may or may not have symptoms of low
magnesium. Tell your doctor right away if you
develop any of these symptoms:
• seizures
• dizziness
• abnormal or fast heart beat
• jitteriness
• jerking movements or shaking (tremors)
• muscle weakness
• spasms of the hands and feet
• cramps or muscle aches
• spasm of the voice box
Your doctor may check the level of magnesium in
your body before you start taking PRILOSEC or during
treatment if you will be taking PRILOSEC for a long
period of time.
The most common side effects with PRILOSEC in adults and
children include:
• headache
• stomach pain
• nausea
• diarrhea
• vomiting
• gas
In addition to the side effects listed above, the most
common side effects in children 1 to 16 years of age
include:
• respiratory system events
• fever
Other side effects:
Serious allergic reactions. Tell your doctor if you get any
of the following symptoms with PRILOSEC:
• rash
• face swelling
• throat tightness
•
difficulty breathing
Your doctor may stop PRILOSEC if these symptoms happen.
45
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your doctor if you have any side effect that bothers you
or that do not go away. These are not all the possible side
effects with PRILOSEC.
Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
How should I store PRILOSEC?
• Store PRILOSEC Delayed-Release Capsules at room
temperature between 59°F to 86°F (15°C to 30°C).
• Store PRILOSEC For Delayed-Release Oral Suspension at
room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the container of PRILOSEC Delayed-Release
Capsules closed tightly.
• Keep the container of PRILOSEC Delayed-Release
Capsules dry and away from light.
Keep PRILOSEC and all medicines out of the reach of
children.
General information about PRILOSEC
Medicines are sometimes prescribed for purposes other than
those listed in a Medication Guide. Do not use PRILOSEC for
a condition for which it was not prescribed. Do not give
PRILOSEC to other people, even if they have the same
symptoms you have. It may harm them.
This Medication Guide summarizes the most important
information about PRILOSEC. For more information, ask
your doctor. You can ask your doctor or pharmacist for
information that is written for healthcare professionals.
For more information, go to www.astrazeneca-us.com or call
1-800-236-9933.
Instructions for Use
For instructions on taking Delayed-Release Capsules, please
see “How should I take PRILOSEC?”
Take PRILOSEC For Delayed-Release Oral Suspension as
follows:
• PRILOSEC For Delayed-Release Oral Suspension
comes in packets containing 2.5 mg and 10 mg
strengths.
• You should use an oral syringe to measure the
amount of water needed to mix your dose. Ask your
pharmacist for an oral syringe.
46
Reference ID: 3675793
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a container, then add the contents of the packet
containing your prescribed dose.
• If you or your child are instructed to use more than
one packet for your prescribed dose, follow the
mixing instructions provided by your pharmacist or
doctor.
• Stir.
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes. If not used within
30 minutes, throw away this dose and mix a new
dose.
• If any medicine remains after drinking, add more
water, stir, and drink right away.
PRILOSEC For Delayed-Release Oral Suspension may be
given through a nasogastric tube (NG tube) or gastric tube,
as prescribed by your doctor. Follow the instructions below:
PRILOSEC For Delayed-Release Oral Suspension:
• PRILOSEC For Delayed-Release Oral Suspension
comes in packets containing 2.5 mg and 10 mg
strengths.
• Use only a catheter tipped syringe to give PRILOSEC
through a NG tube or gastric tube (French size 6 or
larger).
• If your prescribed dose is 2.5 mg, add 5 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• If your prescribed dose is 10 mg, add 15 mL of water
to a catheter tipped syringe, then add the contents of
the packet containing your prescribed dose.
• Shake the syringe right away and then leave it for 2
to 3 minutes to thicken.
• Shake the syringe and give the medicine through the
NG or gastric tube within 30 minutes.
• Refill the syringe with the same amount of water
(either 5 mL or 15 mL of water depending on your
dose).
• Shake the syringe and flush any remaining medicine
from the NG tube or gastric tube into the stomach.
What are the ingredients in PRILOSEC?
Active ingredient in PRILOSEC Delayed-Release
Capsules: omeprazole
Inactive ingredients in PRILOSEC Delayed-Release
Capsules: cellulose, disodium hydrogen phosphate,
47
Reference ID: 3675793
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For current labeling information, please visit https://www.fda.gov/drugsatfda
hydroxypropyl cellulose, hypromellose, lactose, mannitol,
sodium lauryl sulfate. Capsule shells: gelatin-NF, FD&C Blue
#1, FD&C Red #40, D&C Red #28, titanium dioxide,
synthetic black iron oxide, isopropanol, butyl alcohol, FD&C
Blue #2, D&C Red #7 Calcium Lake, and, in addition, the 10
mg and 40 mg capsule shells also contain D&C Yellow #10.
Active ingredient in PRILOSEC For Delayed-Release
Oral Suspension: omeprazole magnesium
Inactive ingredients in PRILOSEC For Delayed-Release
Oral Suspension: glyceryl monostearate, hydroxypropyl
cellulose, hypromellose, magnesium stearate, methacrylic
acid copolymer C, polysorbate, sugar spheres, talc, and
triethyl citrate.
Inactive granules in PRILOSEC For Delayed-Release
Oral Suspension: citric acid, crospovidone, dextrose,
hydroxypropyl cellulose, iron oxide and xantham gum.
This Medication Guide and Instructions for Use has been
approved by the U.S. Food and Drug Administration.
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Revised December 2014
PRILOSEC is a registered trademark of the AstraZeneca
group of companies.
©2014 AstraZeneca Pharmaceuticals LP. All rights reserved.
48
Reference ID: 3675793
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|
custom-source
|
2025-02-12T13:45:59.719385
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022056s017lbl019810s101lbl.pdf', 'application_number': 19810, 'submission_type': 'SUPPL ', 'submission_number': 101}
|
11,737
|
NDA 18-754/S-027, 19-816/S-010
Page 3
®
Orudis®
[o´´roo´dis]
(ketoprofen)
Capsules
Oruvail®
[or´ü vāl]
(ketoprofen)
Extended-Release Capsules
] only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients
with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See
WARNINGS and CLINICAL TRIALS).
• Orudis and Oruvail are contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (See WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal (GI) events (See WARNINGS).
DESCRIPTION
Ketoprofen is a nonsteroidal anti-inflammatory drug. The chemical name for ketoprofen is
2-(3-benzoylphenyl)-propionic acid with the following structural formula:
Its empirical formula is C16H14O3, with a molecular weight of 254.29. It has a pKa of 5.94 in
methanol:water (3:1) and an n-octanol:water partition coefficient of 0.97 (buffer pH 7.4).
Ketoprofen is a white or off-white, odorless, nonhygroscopic, fine to granular powder, melting at about
95° C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong
alkali, but practically insoluble in water at 20° C.
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Orudis®(ketoprofen) capsules contain 25 mg, 50 mg, or 75 mg of ketoprofen for oral administration.
The inactive ingredients present are D&C Yellow 10, FD&C Blue 1, FD&C Yellow 6, gelatin, lactose,
magnesium stearate, and titanium dioxide. The 25 mg dosage strength also contains D&C Red 28 and
FD&C Red 40.
Each Oruvail®(ketoprofen) 100 mg, 150 mg, or 200 mg capsule contains ketoprofen in the form of
hundreds of coated pellets. The dissolution of the pellets is pH dependent, with optimum dissolution
occurring at pH 6.5 - 7.5. There is no dissolution at pH 1.
In addition to the active ingredient, each 100 mg, 150 mg, or 200 mg capsule of Oruvail contains the
following inactive ingredients: D&C Red 22, D&C Red 28, FD&C Blue 1, ethyl cellulose, gelatin,
shellac, silicon dioxide, sodium lauryl sulfate, starch, sucrose, talc, titanium dioxide, and other
proprietary ingredients. The 100 and 150 mg capsules also contain D&C Yellow 10 and FD&C Green
3.
CLINICAL PHARMACOLOGY
Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic properties.
The anti-inflammatory, analgesic, and antipyretic properties of ketoprofen have been demonstrated in
classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to
have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as
well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other
nonsteroidal anti-inflammatory drugs, is not fully understood.
PHARMACODYNAMICS
Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The
enantiomers have similar concentration time curves and do not appear to interact with one another.
An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain
study with Orudis. The effect-site rate constant (ke0) was estimated to be 0.9 hour-1 (95% confidence
limits: 0 to 2.1), and the concentration (Ce50) of ketoprofen that produced one-half the maximum PID
(pain intensity difference) was 0.3 µg/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68%
of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes
following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured
by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.
PHARMACOKINETICS
General
Orudis and Oruvail capsules both contain ketoprofen. They differ only in their release characteristics.
Orudis capsules release drug in the stomach whereas the pellets in Oruvail capsules are designed to
resist dissolution in the low pH of gastric fluid but release drug at a controlled rate in the higher pH
environment of the small intestine (see “DESCRIPTION”).
Irrespective of the pattern of release, the systemic availability (Fs) when either oral formulation is
compared with IV administration is approximately 90% in humans. For 75 to 200 mg single doses, the
area under the curve has been shown to be dose proportional. The figure depicts the plasma time
curves associated with both products.
Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.
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Separate sections follow which delineate differences between Orudis and Oruvail capsules.
Absorption
Orudis capsules — Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within
0.5 to 2 hours.
Oruvail capsules — Ketoprofen is also well-absorbed from this dosage form, although an observable
increase in plasma levels does not occur until approximately 2 to 3 hours after taking the formulation.
Peak plasma levels are usually reached 6 to 7 hours after dosing. (See Figure and Table, below).
When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the
rate of absorption from either dosage form is slowed.
Orudis capsules — Food intake reduces Cmax by approximately one-half and increases the mean time to
peak concentration (tmax) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed
subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian
changes in the absorption process.
Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with
absorption of ketoprofen from Orudis capsules.
Oruvail capsules — Administration of Oruvail with a high-fat meal causes a delay of about 2 hours in
reaching the Cmax; neither the total bioavailability (AUC) nor the Cmax is affected. Circadian changes in
the absorption process have not been studied.
The administration of antacids or other drugs which may raise stomach pH would not be expected to
change the rate or extent of absorption of ketoprofen from Oruvail capsules.
Multiple Dosing
Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment
with Orudis or Oruvail capsules. In studies with healthy male volunteers, trough levels at 24 hours
following administration of Oruvail 200 mg capsules were 0.4 mg/L compared with 0.07 mg/L at 24
hours following administration of Orudis 50 mg capsules QID (12 hours), or 0.13 mg/L following
administration of Orudis 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma
concentration, the accumulation of ketoprofen after multiple doses of Oruvail or Orudis capsules is
minimal.
The figure below shows a reduction in peak height and area after the second 50 mg dose. This is
probably due to a combination of food effects, circadian effects, and plasma sampling times. It is
unclear to what extent each factor contributes to the loss of peak height and area.
The shaded area represents ±1 standard deviation (S.D.) around the mean for Orudis or Oruvail.
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KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING 200 MG OF
ORUVAIL ONCE A DAY (QD), OR ORUDIS 50 MG EVERY 4 HOURS FOR 16 HOURS
COMPARISON OF PHARMACOKINETIC PARAMETERS# FOR ORUDIS AND ORUVAIL
Orudis
Oruvail
Kinetic Parameters
(4 x 50 mg)
(1 x 200 mg)
Extent of oral absorption (bioavailability) Fs (%)
~90
~90
Peak plasma levels Cmax (mg/L)
Fasted
3.9 ± 1.3
3.1 ± 1.2
Fed
2.4 ± 1.0
3.4 ± 1.3
Time to peak concentration tmax (h)
Fasted
1.2 ± 0.6
6.8 ± 2.1
Fed
2.0 ± 0.8
9.2 ± 2.6
Area under plasma concentration-time curve
AUC0-24h (mg•h/L)
Fasted
32.1 ± 7.2
30.1 ± 7.9
Fed
36.6 ± 8.1
31.3 ± 8.1
Oral-dose clearance CL/F (L/h)
6.9 ± 0.8
6.8 ± 1.8
Half-life t1/2 (h)
2.1 ± 1.2
5.4 ± 2.2
[See footnote 1]
# Values expressed are mean ± standard deviation
1 In the case of Oruvail, absorption is slowed, intrinsic clearance is unchanged, but because the rate of
elimination is dependent on absorption, the half-life is prolonged.
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Metabolism
The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The
glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a
potential reservoir for parent drug, and this may be important in persons with renal insufficiency,
whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent
drug (see “Special Populations: Renally impaired”). The conjugates are reported to appear only in
trace amounts in plasma in healthy adults, but are higher in elderly subjects — presumably because of
reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses
(50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively,
for the S & R enantiomers.
There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-
metabolizing enzymes.
Elimination
The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd of 0.1 L/kg after IV
administration. The elimination half-life of ketoprofen has been reported to be 2.05 ± 0.58 h (Mean ±
S.D.) following IV administration, from 2 to 4 h following administration of Orudis capsules, and 5.4
± 2.2 h after administration of Oruvail 200 mg capsules. In cases of slow drug absorption, the
elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears
prolonged.
After a single 200 mg dose of Oruvail, the plasma levels decline slowly, and average 0.4 mg/L after 24
hours (see Figure above).
In a 24-hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine,
primarily as the glucuronide metabolite.
Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been
measured to confirm this.
Special Populations
Elderly: Clearance and unbound fraction
The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared
to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC
increase with increasing age. In addition, there is a corresponding increase in unbound fraction with
increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not
been determined whether age-related changes in absorption among the elderly contribute to the
changes in bioavailability of ketoprofen (see “Geriatric Use”).
Orudis (ketoprofen) capsules — In a study conducted with young and elderly men and women, results
for subjects older than 75 years of age showed that free drug AUC increased by 40% and Cmax
increased by 60% as compared with estimates of the same parameters in young subjects (those younger
than 35 years of age; see “INDIVIDUALIZATION OF DOSAGE DOSAGE AND
ADMINISTRATION”).
Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life
was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction
associated with aging.
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Oruvail (ketoprofen) capsules — The effects of age and gender on ketoprofen disposition were
investigated in 2 small studies in which elderly male and female subjects received Oruvail 200 mg
capsules. The results were compared with those from another study conducted in healthy young men.
Compared to the younger subject group, the elimination half-life in the elderly was prolonged by 54%
and total drug Cmax and AUC were 40% and 70% higher, respectively. Plasma concentrations in the
elderly after single doses and at steady state were essentially the same. Thus, no drug accumulation
occurs.
In comparison to younger subjects taking the immediate-release formulation (Orudis), there was a
decrease of 16% and 25% in total drug Cmax and AUC, respectively, among the elderly. Free drug data
are not available for Oruvail.
Renally impaired
Studies of the effects of renal-function impairment have been small. They indicate a decrease in
clearance in patients with impaired renal function. In 23 patients with renal impairment, free
ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was
reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function,
and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination t1/2
was prolonged from 1.6 hours in normal subjects to approximately 3 hours in patients with mild renal
impairment, and to approximately 5 to 9 hours in patients with moderately to severely impaired renal
function.
No studies have been conducted in patients with renal impairment taking Oruvail capsules (see
“INDIVIDUALIZATION OF DOSAGE DOSAGE AND ADMINISTRATION”).
Hepatically impaired
For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of Orudis
capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was
0.07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that
observed for normal subjects. However, the unbound (biologically active) fraction was approximately
doubled, probably due to hypoalbuminemia and high variability which was observed in the
pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and
daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect.
No studies have been conducted in patients with hepatic impairment taking Oruvail capsules (see
“INDIVIDUALIZATION OF DOSAGE DOSAGE AND ADMINISTRATION”).
CLINICAL TRIALS
Rheumatoid Arthritis and Osteoarthritis
The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and
osteoarthritis. Using standard assessments of therapeutic response, there were no detectable differences
in effectiveness or in the incidence of adverse events in crossover comparison of Orudis (ketoprofen)
and Oruvail (ketoprofen). In other trials, ketoprofen demonstrated effectiveness comparable to aspirin,
ibuprofen, naproxen, piroxicam, diclofenac and indomethacin. In some of these studies there were
more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on
other NSAIDs.
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In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with
gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results
comparable to those seen with control nonsteroidal drugs.
Management of Pain
The effectiveness of Orudis as a general-purpose analgesic has been studied in standard pain models
which have shown the effectiveness of doses of 25 to 150 mg. Doses of 25 mg were superior to
placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but
there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of
dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 to 75 mg did not
have increased analgesic effect. Studies in postoperative pain have shown that Orudis in doses of
25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of
acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak
pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer,
particularly with the higher doses of ketoprofen.
The use of Oruvail in patients with acute pain is not recommended, since, in comparison to Orudis,
Oruvail would be expected to have a delayed analgesic response due to its extended-release
characteristics.
INDIVIDUALIZATION OF DOSAGE
The recommended starting dose of ketoprofen in otherwise healthy patients is Orudis, 75 mg three
times or 50 mg four times a day, or Oruvail, 200 mg administered once a day. Smaller doses of Orudis
or Oruvail should be utilized initially in small individuals or in debilitated or elderly patients. The
recommended maximum daily dose of ketoprofen is 300 mg/day for Orudis or 200 mg/day for Oruvail.
Concomitant use of Orudis and Oruvail is not recommended.
If minor side effects appear, they may disappear at a lower dose which may still have an adequate
therapeutic effect. If well tolerated but not optimally effective, the dosage may be increased. Individual
patients may show a better response to 300 mg of Orudis daily as compared to 200 mg, although in
well-controlled clinical trials patients on 300 mg did not show greater mean effectiveness. They did,
however, show an increased frequency of upper- and lower-GI distress and headaches. It is of interest
that women also had an increased frequency of these adverse effects compared to men. When treating
patients with 300 mg/day, the physician should observe sufficient increased clinical benefit to offset
potential increased risk.
In patients with mildly impaired renal function, the maximum recommended total daily dose of Orudis
or Oruvail is 150 mg. In patients with a more severe renal impairment (GFR less than
25 mL/min/1.73 m2 or end-stage renal impairment), the maximum total daily dose of Orudis or Oruvail
should not exceed 100 mg.
In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or
BUN levels. Therefore, it is recommended that the initial dosage of Orudis or Oruvail should be
reduced for patients over 75 years of age (see “Geriatric Use”).
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It is recommended that for patients with impaired liver function and serum albumin concentration less
than 3.5 g/dL, the maximum initial total daily dose of Orudis or Oruvail should be 100 mg. All patients
with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function,
may have increased levels of free (biologically active) ketoprofen and should be closely monitored.
The dosage may be increased to the range recommended for the general population, if necessary, only
after good individual tolerance has been ascertained.
Because hypoalbuminemia and reduced renal function both increase the fraction of free drug
(biologically active form), patients who have both conditions may be at greater risk of adverse effects.
Therefore, it is recommended that such patients also be started on lower doses of Orudis or Oruvail and
closely monitored.
As with other nonsteroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are
gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that Orudis or
Oruvail be taken with antacids, food, or milk. Although food delays the absorption of both
formulations (see “CLINICAL PHARMACOLOGY”), in most of the clinical trials ketoprofen was
taken with food or milk.
Physicians may want to make specific recommendations to patients about when they should take
Orudis or Oruvail in relation to food and/or what patients should do if they experience minor GI
symptoms associated with either formulation.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Orudis and Oruvail and other treatment options
before deciding to use Orudis and Oruvail. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).
Orudis and Oruvail are indicated for the management of the signs and symptoms of rheumatoid
arthritis and osteoarthritis.
Oruvail is not recommended for treatment of acute pain because of its extended-release characteristics
(see “PHARMACOKINETICS”).
Orudis is indicated for the management of pain. Orudis is also indicated for treatment of primary
dysmenorrhea.
CONTRAINDICATIONS
Orudis and Oruvail are contraindicated in patients who have shown hypersensitivity to ketoprofen.
Orudis and Oruvail should not be given to patients who have experienced asthma, urticaria, or allergic-
type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic reactions to
ketoprofen have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and
PRECAUTIONS – Preexisting Asthma).
Orudis and Oruvail are contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
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WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see WARNINGS – Gastrointestinal Effects: Risk of
Ulceration, Bleeding, and Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Hypertension
NSAIDs, including Orudis and Oruvail, can lead to onset of new hypertension or worsening of pre-
existing hypertension, either of which may contribute to the increased incidence of CV events. Patients
taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including Orudis and Oruvail, should be used with caution in patients with hypertension.
Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and
throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has
been observed in approximately 2% of patients taking ketoprofen. Orudis and Oruvail should be used
with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation
NSAIDs, including Orudis and Oruvail, can cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large
intestine, which can be fatal. These serious adverse events can occur at any time, with or without
warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious
upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or
perforation appear tocaused by NSAIDs occur in approximately 1% of patients treated for 3 to 6
months, and in about 2-4% of patients treated for one year.These trends continue with longer duration
of use, increasing the likelihood of developing a serious GI event at some time during the course of
therapy. However, even short-term therapy is not without risk.
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NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk for GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should
include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk
patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Orudis or Oruvail in
patients with advanced renal disease. Therefore, treatment with Orudis or Oruvail is not recommended
in these patients with advanced renal disease. If Orudis or Oruvail therapy must be initiated, close
monitoring of the patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
Orudis or Oruvail. Orudis or Oruvail should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including Orudis and Oruvail, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should be informed about the signs
and symptoms of serious skin manifestations and use of the drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.
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Pregnancy
In late pregnancy, as with other NSAIDs, Orudis and Oruvail should be avoided because they may
cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Orudis and Oruvail cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
If steroid dosage is reduced or eliminated during therapy, it should be reduced slowly and the patients
observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation
of symptoms of arthritis.
The pharmacological activity of Orudis and Oruvail in reducing [fever and] inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious,
painful conditions.
Ketoprofen and other nonsteroidal anti-inflammatory drugs cause nephritis in mice and rats associated
with chronic administration. Rare cases of interstitial nephritis or nephrotic syndrome have been
reported in humans with ketoprofen since it has been marketed.
A second form of renal toxicity has been seen in patients with conditions leading to a reduction in renal
blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of
renal blood flow. In these patients, administration of a nonsteroidal anti-inflammatory drug results in a
dose-dependent decrease in prostaglandin synthesis and, secondarily, in renal blood flow which may
precipitate overt renal failure. Patients at greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is typically followed by recovery to the pretreatment
state.
Since ketoprofen is primarily eliminated by the kidneys and its pharmacokinetics are altered by renal
failure (see “CLINICAL PHARMACOLOGY”), patients with significantly impaired renal function
should be closely monitored, and a reduction of dosage should be anticipated to avoid accumulation of
ketoprofen and/or its metabolites (see “INDIVIDUALIZATION OF DOSAGEDOSAGE AND
ADMINISTRATION”).
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including Orudis and Oruvail. These laboratory abnormalities may progress, may remain unchanged,
or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three
or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, and fatal
fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
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A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with Orudis or Oruvail. If clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Orudis or Oruvail should be
discontinued.
In patients with chronic liver disease with reduced serum albumin levels, ketoprofen’s
pharmacokinetics are altered (see “CLINICAL PHARMACOLOGY”). Such patients should be
closely monitored, and a reduction of dosage should be anticipated to avoid high blood levels of
ketoprofen and/or its metabolites (see “INDIVIDUALIZATION OF DOSAGEDOSAGE AND
ADMINISTRATION”).
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Orudis and Oruvail. This may be
due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon
erythropoiesis. Patients on long-term treatment with NSAIDs, including Orudis or Oruvail, should
have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving Orudis or Oruvail who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants, should be carefully
monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, Orudis or Oruvail should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. Orudis or Oruvail, like other NSAIDs, may cause serious CV side effects, such as MI or stroke,
which may result in hospitalization and even death. Although serious CV events can occur
without warning symptoms, patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for medical advice when
observing any indicative sign or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS – Cardiovascular Effects).
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2. Orudis and Oruvail, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms,
patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask
for medical advice when observing any indicative sign or symptoms including epigastric pain,
dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this
follow-up (see “WARNINGS Gastrointestinal Effects: Risk of Ulceration, Bleeding, and
Perforation”).
3. Orudis and Oruvail, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although
serious skin reactions may occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and
should ask for medical advice when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of rash and contact
their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, Orudis and Oruvail should be avoided because it may
cause premature closure of the ductus arteriosus.
NSAIDs are often essential agents in the management of arthritis and have a major role in the
treatment of pain, but they also may be commonly employed for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see “WARNINGS,”
“PRECAUTIONS,” and “ADVERSE REACTIONS” sections) and likely benefits of NSAID
treatment, particularly when the drugs are used for less serious conditions where treatment without
NSAIDs may represent an acceptable alternative to both the patient and physician.
Because aspirin causes an increase in the level of unbound ketoprofen, patients should be advised not
to take aspirin while taking ketoprofen (see “Drug Interactions”). It is possible that minor adverse
symptoms of gastric intolerance may be prevented by administering Orudis with antacids, food or
milk. Oruvail has not been studied with antacids. Because food and milk do affect the rate but not the
extent of absorption (see “CLINICAL PHARMACOLOGY”), physicians may want to make specific
recommendations to patients about when they should take ketoprofen in relation to food and/or what
patients should do if they experience minor GI symptoms associated with ketoprofen therapy.
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Laboratory Tests
Because serious GI-tract ulceration and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs,
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, Orudis and Oruvail should be discontinued.
Drug Interactions
The following drug interactions were studied with ketoprofen doses of 200 mg/day. The possibility of
increased interaction should be kept in mind when Orudis doses greater than 50 mg as a single dose or
200 mg of ketoprofen per day are used concomitantly with highly bound drugs.
1.
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This
interaction should be given consideration in patients taking NSAIDs concomitantly with
ACE-inhibitors.
2.
Antacids
Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with
the rate or extent of the absorption of ketoprofen administered as Orudis.
3.
Aspirin
Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent
administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma
clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin. The clinical significance of
these changes is not known; however, as with other NSAIDs, concomitant administration of
ketoprofen and aspirin is not generally recommended because of the potential of increased adverse
effects.
4.
Diuretics
NSAIDs can reduce the natriuetic effect of furosemide and thiazides in some patients.
Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium
and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at a greater
risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin
inhibition (see “PRECAUTIONS”). During concomitant therapy with NSAIDs, the patient should be
observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure
diuretic efficacy.
5.
Digoxin
In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were
concomitantly administered, ketoprofen did not alter the serum levels of digoxin.
6.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
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7.
Methotrexate
Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to
elevated serum levels of the drug and increased toxicity. NSAIDs have been reported to competitively
inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance
the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly
with methotrexate.
8.
Probenecid
Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen
to about one-third, as well as decreasing its protein binding. Therefore, the combination of ketoprofen
and probenecid is not recommended.
9.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs
together have a risk of serious GI bleeding higher than users of either drug alone. In a short-term
controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of
warfarin on prothrombin time. Bleeding from a number of sites may be a complication of warfarin
treatment and GI bleeding a complication of ketoprofen treatment. Because prostaglandins play an
important role in hemostasis and ketoprofen has an effect on platelet function as well (see
“Drug/Laboratory Test Interactions: Effect on Blood Coagulation”), concurrent therapy with
ketoprofen and warfarin requires close monitoring of patients on both drugs.
Drug/Laboratory Test Interactions:
Effect on Blood Coagulation
Ketoprofen decreases platelet adhesion and aggregation. Therefore, it can prolong bleeding time by
approximately 3 to 4 minutes from baseline values. There is no significant change in platelet count,
prothrombin time, partial thromboplastin time, or thrombin time.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic oral toxicity studies in mice (up to 32 mg/kg/day; 96 mg/m2/day) did not indicate a
carcinogenic potential for ketoprofen. The maximum recommended human therapeutic dose is
300 mg/day for a 60 kg patient with a body surface area of 1.6 m2, which is 5 mg/kg/day or
185 mg/m2/day. Thus the mice were treated at 0.5 times the maximum human daily dose based on
surface area.
A 2-year carcinogenicity study in rats, using doses up to 6.0 mg/kg/day (36 mg/m2/day), showed no
evidence of tumorigenic potential. All groups were treated for 104 weeks except the females receiving
6.0 mg/kg/day (36 mg/m2/day) where the drug treatment was terminated in week 81 because of low
survival; the remaining rats were sacrificed after week 87. Their survival in the groups treated for 104
weeks was within 6% of the control group. An earlier 2-year study with doses up to
12.5 mg/kg/day (75 mg/m2/day) also showed no evidence of tumorigenicity, but the survival rate was
low and the study was therefore judged inconclusive. Ketoprofen did not show mutagenic potential in
the Ames Test. Ketoprofen administered to male rats (up to 9 mg/kg/day; or 54 mg/m2/day) had no
significant effect on reproductive performance or fertility. In female rats administered 6 or
9 mg/kg/day (36 or 54 mg/m2/day), a decrease in the number of implantation sites has been noted. The
dosages of 36 mg/m2/day in rats represent 0.2 times the maximum recommended human dose of
185 mg/m2/day (see above).
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Abnormal spermatogenesis or inhibition of spermatogenesis developed in rats and dogs at high doses,
and a decrease in the weight of the testes occurred in dogs and baboons at high doses.
Pregnancy
Teratogenic Effects: Pregnancy Category C
In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m2/day)
and rats at doses up to 9 mg/kg/day (54 mg/m2/day), the approximate equivalent of 0.2 times the
maximum recommended therapeutic dose of 185 mg/m2/day, showed no teratogenic or embryotoxic
effects. In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but
not teratogenicity. However, animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies in pregnant women. Orudis or Oruvail should be
used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
Labor and Delivery
The effects of ketoprofen on labor and delivery in pregnant women are unknown. Studies in rats have
shown ketoprofen at doses of 6 mg/kg (36 mg/m2/day, approximately equal to 0.2 times the maximum
recommended human dose) prolongs pregnancy when given before the onset of labor. Because of the
known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus
arteriosus), use of ketoprofen during late pregnancy should be avoided.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Data on secretion in human milk after
ingestion of ketoprofen do not exist. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m2/day;
approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development.
Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of
the plasma drug level. As with other drugs that are excreted in milk, ketoprofen is not recommended
for use in nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients blow the age of 18 have not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving Orudis or
Oruvail, compared with younger patients. Peak ketoprofen concentrations and free drug AUC were
increased in older patients (see “Special Populations”). The glucuronide conjugate of ketoprofen,
which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by
the kidney. Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection. It is recommended that the initial dosage of Orudis or Oruvail should be
reduced for patients over 75 years of age and it may be useful to monitor renal function (see
“INDIVIDUALIZATION OF DOSAGEDOSAGE AND ADMINISTRATION”). In addition, the
risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly
patients may be more sensitive to the antiprostaglandin effects of NSAIDS (on the gastrointestinal tract
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and kidneys) than younger patients (see “WARNINGS” and “PRECAUTIONS”). In particular,
elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration
or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this
population. Therefore, caution should be exercised in treating the elderly, and when individualizing
their dosage, extra care should be taken when increasing the dose (see “INDIVIDUALIZATION OF
DOSAGEDOSAGE AND ADMINISTRATION”).
In Orudis clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369
(24%) were ≥65 years of age, and 92 (6%) were ≥75 years of age. For Orudis acute pain studies, 23
(5%) of 484 patients were ≥60 years of age. In Oruvail clinical studies, 356 (42%) of 840 osteoarthritis
or rheumatoid arthritis patients were ≥65 years of age, and less than 100 of these were ≥75 years of
age. No overall differences in effectiveness were observed between these patients and younger
patients.
ADVERSE REACTIONS
The incidence of common adverse reactions (above 1%) was obtained from a population of 835
Orudis-treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 Oruvail-treated
(200 mg/day) patients in trials lasting from 4 to 16 weeks.
Minor gastrointestinal side effects predominated; upper gastrointestinal symptoms were more common
than lower gastrointestinal symptoms. In crossover trials in 321 patients with rheumatoid arthritis or
osteoarthritis, there was no difference in either upper or lower gastrointestinal symptoms between
patients treated with 200 mg of Oruvail (ketoprofen) once a day or 75 mg of Orudis (ketoprofen)
TID (225 mg/day). Peptic ulcer or GI bleeding occurred in controlled clinical trials in less than 1% of
1,076 patients; however, in open label continuation studies in 1,292 patients the rate was greater than
2%.
The incidence of peptic ulceration in patients on NSAIDs is dependent on many risk factors including
age, sex, smoking, alcohol use, diet, stress, concomitant drugs such as aspirin and corticosteroids, as
well as the dose and duration of treatment with NSAIDs (see “WARNINGS”).
Gastrointestinal reactions were followed in frequency by central nervous system side effects, such as
headache, dizziness, or drowsiness. The incidence of some adverse reactions appears to be dose-related
(see “DOSAGE AND ADMINISTRATION”). Rare adverse reactions (incidence less than 1%) were
collected from one or more of the following sources: foreign reports to manufacturers and regulatory
agencies, publications, U.S. clinical trials, and/or U.S. postmarketing spontaneous reports.
Reactions are listed below under body system, then by incidence or number of cases in decreasing
incidence.
Incidence Greater than 1% (Probable Causal Relationship)
Digestive: Dyspepsia (11%), nausea*, abdominal pain*, diarrhea*, constipation*, flatulence*,
anorexia, vomiting, stomatitis.
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Nervous System: Headache*, dizziness, CNS inhibition (i.e., pooled reports of somnolence, malaise,
depression, etc.) or excitation (i.e., insomnia, nervousness, dreams, etc.)*.
Special Senses: Tinnitus, visual disturbance.
Skin and Appendages: Rash.
Urogenital: Impairment of renal function (edema, increased BUN)*, signs or symptoms of urinary-
tract irritation.
* Adverse events occurring in 3 to 9% of patients.
Incidence Less than 1% (Probable Causal Relationship)
Body as a Whole: Chills, facial edema, infection, pain, allergic reaction, anaphylaxis.
Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular
disease, vasodilation.
Digestive: Appetite increased, dry mouth, eructation, gastritis, rectal hemorrhage, melena, fecal occult
blood, salivation, peptic ulcer, gastrointestinal perforation, hematemesis, intestinal ulceration, hepatic
dysfunction, hepatitis, cholestatic hepatitis, jaundice.
Hemic: Hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia.
Metabolic and Nutritional: Thirst, weight gain, weight loss, hyponatremia.
Musculoskeletal: Myalgia.
Nervous System: Amnesia, confusion, impotence, migraine, paresthesia, vertigo.
Respiratory: Dyspnea, hemoptysis, epistaxis, pharyngitis, rhinitis, bronchospasm, laryngeal edema.
Skin and Appendages: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, bullous rash,
exfoliative dermatitis, photosensitivity, skin discoloration, onycholysis, toxic epidermal necrolysis,
erythema multiforme, Stevens-Johnson syndrome.
Special Senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal hemorrhage
and pigmentation change, taste perversion.
Urogenital: Menometrorrhagia, hematuria, renal failure, interstitial nephritis, nephrotic syndrome.
Incidence Less than 1% (Causal Relationship Unknown)
The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being
listed to serve as alerting information to the physician.
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Body as a Whole: Septicemia, shock.
Cardiovascular: Arrhythmias, myocardial infarction.
Digestive: Buccal necrosis, ulcerative colitis, microvesicular steatosis, pancreatitis.
Endocrine: Diabetes mellitus (aggravated).
Nervous System: Dysphoria, hallucination, libido disturbance, nightmares, personality disorder, aseptic
meningitis.
Urogenital: Acute tubulopathy, gynecomastia.
OVERDOSAGE
Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness,
nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Respiratory
depression, coma, or convulsions have occurred following large ketoprofen overdoses. Gastrointestinal
bleeding, hypotension, hypertension, or acute renal failure may occur, but are rare.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Gut decontamination may be indicated in patients with symptoms seen within
4 hours (longer for sustained-release products) or following a large overdose (5 to 10 times the usual
dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults,
1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose. Forced diuresis,
alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to
ketoprofen’s high protein binding.
Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults. Five
of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child). A 12-year-old girl had
tonic-clonic convulsions 1-2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets
of acetaminophen with hydrocodone. Her ketoprofen level was 1128 mg/L (56 times the upper
therapeutic level of 20 mg/L) 3-4 hours post ingestion. Full recovery ensued 18 hours after ingestion
following management with intubation, diazepam, and activated charcoal. A 45-year-old woman
ingested twelve 200 mg Oruvail and 375 mL vodka, was treated with emesis and supportive measures
2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.
DOSAGE AND ADMINISTRATION
Rheumatoid Arthritis and Osteoarthritis
Carefully consider the potential benefits and risks of Orudis and Oruvail and other treatment options
before deciding to use Orudis and Oruvail. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with Orudis and Oruvail, the dose and frequency should
be adjusted to suit an individual patient’s needs.
Concomitant use of Orudis and Oruvail is not recommended.
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If minor side effects appear, they may disappear at a lower dose which may still have an adequate
therapeutic effect. If well tolerated but not optimally effective, the dosage may be increased. Individual
patients may show a better response to 300 mg of Orudis daily as compared to 200 mg, although in
well-controlled clinical trials patients on 300 mg did not show greater mean effectiveness. They did,
however, show an increased frequency of upper- and lower-GI distress and headaches. It is of interest
that women also had an increased frequency of these adverse effects compared to men. When treating
patients with 300 mg/day, the physician should observe sufficient increased clinical benefit to offset
potential increased risk.
In patients with mildly impaired renal function, the maximum recommended total daily dose of Orudis
or Oruvail is 150 mg. In patients with a more severe renal impairment (GFR less than
25 mL/min/1.73 m2 or end-stage renal impairment), the maximum total daily dose of Orudis or Oruvail
should not exceed 100 mg.
In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or
BUN levels. Therefore, it is recommended that the initial dosage of Orudis or Oruvail should be
reduced for patients over 75 years of age (see “Geriatric Use”).
It is recommended that for patients with impaired liver function and serum albumin concentration less
than 3.5 g/dL, the maximum initial total daily dose of Orudis or Oruvail should be 100 mg. All patients
with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function,
may have increased levels of free (biologically active) ketoprofen and should be closely monitored.
The dosage may be increased to the range recommended for the general population, if necessary, only
after good individual tolerance has been ascertained.
Because hypoalbuminemia and reduced renal function both increase the fraction of free drug
(biologically active form), patients who have both conditions may be at greater risk of adverse effects.
Therefore, it is recommended that such patients also be started on lower doses of Orudis or Oruvail and
closely monitored.
Rheumatoid Arthritis and Osteoarthritis
The recommended starting dose of ketoprofen in otherwise healthy patients is for Orudis 75 mg three
times or 50 mg four times a day, or for Oruvail 200 mg administered once a day. Smaller doses of
Orudis or Oruvail should be utilized initially in small individuals or in debilitated or elderly patients.
The recommended maximum daily dose of ketoprofen is 300 mg/day for Orudis or 200 mg/day for
Oruvail (see “INDIVIDUALIZATION OF DOSAGE”).
Dosages higher than 300 mg/day of Orudis or 200 mg/day of Oruvail are not recommended because
they have not been studied. Concomitant use of Orudis and Oruvail is not recommended. Relatively
smaller people may need smaller doses (see “INDIVIDUALIZATION OF DOSAGE”).
As with other nonsteroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are
gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that Orudis or
Oruvail be taken with antacids, food, or milk. Although food delays the absorption of both
formulations (see “CLINICAL PHARMACOLOGY”), in most of the clinical trials ketoprofen was
taken with food or milk.
Physicians may want to make specific recommendations to patients about when they should take
Orudis or Oruvail in relation to food and/or what patients should do if they experience minor GI
symptoms associated with either formulation.
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Management of Pain and Dysmenorrhea
The usual dose of Orudis recommended for mild-to-moderate pain and dysmenorrhea is 25 to 50 mg
every 6 to 8 hours as necessary. A smaller dose should be utilized initially in small individuals, in
debilitated or elderly patients, or in patients with renal or liver disease (see “PRECAUTIONS”). A
larger dose may be tried if the patient’s response to a previous dose was less than satisfactory, but
doses above 75 mg have not been shown to give added analgesia. Daily doses above 300 mg are not
recommended because they have not been adequately studied. Because of its typical nonsteroidal anti-
inflammatory drug-side-effect profile, including as its principal adverse effect GI side effects (see
“WARNINGS” and “ADVERSE REACTIONS”), higher doses of Orudis should be used with
caution and patients receiving them observed carefully (see “INDIVIDUALIZATION OF
DOSAGE”).
Oruvail is not recommended for use in treating acute pain because of its extended-release
characteristics.
HOW SUPPLIED
Orudis® (ketoprofen) Capsules are available as follows:
25 mg, NDC 0008-4186, dark-green and red capsule marked “WYETH 4186” on one side and
“ORUDIS 25” on the reverse side, in bottles of 100 capsules.
50 mg, NDC 0008-4181, dark-green and light-green capsule marked “WYETH 4181” on one side and
“ORUDIS 50” on the reverse side, in bottles of 100 capsules.
75 mg, NDC 0008-4187, dark-green and white capsule marked “WYETH 4187” on one side and
“ORUDIS 75” on the reverse side, in bottles of 100 and 500 capsules and in Redipak® cartons of 100
each containing 10 blister strips of 10 capsules.
Oruvail® (ketoprofen) Extended-Release Capsules are available as follows:
100 mg, NDC 0008-0821, opaque pink and dark-green capsule marked with two radial bands and
“ORUVAIL 100” in bottles of 100 capsules.
150 mg, NDC 0008-0822, opaque pink and light-green capsule marked with two radial bands and
“ORUVAIL 150” in bottles of 100 capsules.
200 mg, NDC 0008-0690, opaque pink and off-white capsule marked with two radial bands and
“ORUVAIL 200” in bottles of 100 capsules and in Redipak® cartons each containing 10 blister strips
of 10 capsules.
Keep tightly closed.
Store at room temperature, approximately 25° C (77° F).
Dispense in a tight container.
Oruvail capsules should be protected from direct light and excessive heat and humidity.
The appearance of these capsules is a registered trademark of Wyeth Pharmaceuticals.
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By arrangement with Rhone-Poulenc Rorer France.
Orudis Capsules manufactured and distributed
by Wyeth Pharmaceuticals
Oruvail Capsules distributed by
Wyeth Pharmaceuticals
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
W10460C002
ET01
Rev 07/05
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
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NDA 18-754/S-027, 19-816/S-010
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What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-754/S-027, 19-816/S-010
Page 26
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018754s027,019816s010lbl.pdf', 'application_number': 19816, 'submission_type': 'SUPPL ', 'submission_number': 10}
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ADAGEN®
(pegademase bovine) Injection
DESCRIPTION
ADAGEN
® (pegademase bovine) Injection is a modified enzyme used for enzyme replacement therapy for the treatment of severe
combined immunodeficiency disease (SCID) associated with a deficiency of adenosine deaminase.
ADAGEN
® (pegademase bovine) Injection is supplied in an isotonic, pyrogen free, sterile solution, pH 7.2-7.4, for intramuscular
injection only. The solution is clear and colorless. It is supplied in 1.5 mL single-dose vials.
The chemical name for ADAGEN
® (pegademase bovine) Injection is (monomethoxypolyethylene glycol succinimidyl) 11-17
adenosine deaminase. It is a conjugate of numerous strands of monomethoxypolyethylene glycol (PEG), molecular weight 5,000,
covalently attached to the enzyme adenosine deaminase (ADA). ADA (adenosine deaminase EC 3.5.4.4) used in the manufacture of
ADAGEN
® (pegademase bovine) Injection is derived from bovine intestine.
The structural formula of ADAGEN
® (pegademase bovine) Injection is:
[CH3-(OCH2CH2)x -O-C-CH2CH2-C-NH]y -adenosine deaminase
||
||
O
O
x ≈ 114 oxyethylene groups per PEG strand.
y ≈ 11-17 primary amino groups of lysine onto which succinyl PEG is attached.
Each milliliter of ADAGEN
® (pegademase bovine) Injection contains:
Pegademase bovine ....................................................................................................................................................................... 250 units*
Monobasic sodium phosphate, USP .................................................................................................................................................1.20 mg
Dibasic sodium phosphate, USP........................................................................................................................................................5.58 mg
Sodium Chloride, USP ......................................................................................................................................................................8.50 mg
Water for injection, USP ..........................................................................................................................................................q.s. to 1.0 mL
*One unit of activity is defined as the amount of ADA that converts 1µM of adenosine to inosine per minute at 25°C and pH 7.3.
CLINICAL PHARMACOLOGY
Severe Combined Immunodeficiency Disease Associated with ADA Deficiency
Severe combined immunodeficiency disease (SCID) associated with a deficiency of ADA is a rare, inherited, and often fatal disease.
In the absence of the ADA enzyme, the purine substrates adenosine and 2´-deoxyadenosine accumulate, causing metabolic
abnormalities that are directly toxic to lymphocytes.
The immune deficiency can be cured by bone marrow transplantation. When a suitable bone marrow donor is unavailable or when
bone marrow transplantation fails, non-selective replacement of the ADA enzyme has been provided by periodic irradiated red blood
cell transfusions. However, transmission of viral infections and iron overload are serious risks associated with irradiated red blood cell
transfusions, and relatively few ADA deficient patients have benefitted from chronic transfusion therapy.
ADAGEN
® (pegademase bovine) Injection provides specific and direct replacement of the deficient enzyme, but will not benefit
patients with immunodeficiency due to other causes.
In patients with ADA deficiency, rigorous adherence to a schedule of ADAGEN
® (pegademase bovine) Injection administration can
eliminate the toxic metabolites of ADA deficiency and result in improved immune function. It is imperative that treatment with
ADAGEN
® (pegademase bovine) Injection be carefully monitored by measurement of the level of ADA activity in plasma.
Monitoring of the level of deoxyadenosine triphosphate (dATP) in erythrocytes is also helpful in determining that the dose of
ADAGEN
® (pegademase bovine) Injection is adequate.
Actions
ADAGEN
® (pegademase bovine) Injection provides specific replacement of the deficient enzyme.
In the absence of the enzyme ADA, the purine substrates adenosine, 2´-deoxyadenosine and their metabolites are toxic to
lymphocytes. The direct action of ADAGEN
® (pegademase bovine) Injection is the correction of these metabolic abnormalities.
Improvement in immune function and diminished frequency of opportunistic infections compared with the natural history of combined
immunodeficiency due to ADA deficiency only occurs after metabolic abnormalities are corrected. There is a lag between the
correction of the metabolic abnormalities and improved immune function. This period of time is variable, and has been reported to be
from a few weeks to as long as 6 months. In contrast to the natural history of combined immunodeficiency disease due to ADA
deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in
patients receiving ADAGEN
® (pegademase bovine) Injection.
Pharmacokinetics
The pharmacokinetics and biochemical effects of ADAGEN
® (pegademase bovine) Injection have been studied in six children
ranging in age from 6 weeks to 12 years with SCID associated with ADA deficiency.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After the intramuscular injection of ADAGEN
® (pegademase bovine) Injection, peak plasma levels of ADA activity were reached 2 to
3 days following administration. The plasma elimination half-life of ADA following the administration of ADAGEN
® (pegademase
bovine) Injection was variable, even for the same child. The range was 3 to > 6 days. Following weekly injections of ADAGEN
®
(pegademase bovine) Injection at 15 U/kg, the average trough level of ADA activity in plasma was between 20 and 25 µmol/hr/mL.
Biochemical Effects
The changes in red blood cell deoxyadenosine nucleotide (dATP) and S-adenosylhomocysteine hydrolase (SAHase) have been
evaluated. In patients with ADA deficiency, inadequate elimination of 2´-deoxyadenosine caused a marked elevation in dATP and a
decrease in SAHase level in red blood cells. Prior to treatment with ADAGEN
® (pegademase bovine) Injection, the levels of dATP in
the red blood cells ranged from 0.056 to 0.899 µmol/mL of erythrocytes. After 2 months of maintenance treatment with ADAGEN
®
(pegademase bovine) Injection, the levels decreased to 0.007 to 0.015 µmol/mL. The normal value of dATP is below 0.001 µmol/mL.
In the same period of time, the levels of SAHase increased from the pretreatment range of 0.09 to 0.22 nmol/hr/mg protein to a range
of 2.37 to 5.16 nmol/hr/mg protein. The normal value for SAHase is 4.18 ± 1.9 nmol/hr/mg protein.
The optimal dosage and schedule of administration of ADAGEN
® (pegademase bovine) Injection should be established for each
patient, based on monitoring of plasma ADA activity levels (trough levels before maintenance injection), biochemical markers of
ADA deficiency (primarily red cell dATP content), and parameters of immune function. Since improvement in immune function
follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following
biochemical goals: 1) maintain plasma ADA activity (trough levels) in the range of 15-35 µmol/hr/mL (assayed at 37°C); and 2)
decline in erythrocyte dATP to ≤ 0.005-0.015 µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP
+ dATP) content, with a normal ATP level, as measured in a pre-injection sample.
In vitro immunologic data (lymphocyte response to mitogens and lymphocyte surface antigens) were obtained, but their clinical
significance is unknown. Prior to treatment with ADAGEN
® (pegademase bovine) Injection, immune status was significantly below
normal, as indicated by < 10% of normal mitogen responses and circulating mononuclear cells bearing T-cell surface antigens. These
parameters improved, though not always to normal, within 2 to 6 months of therapy.
INDICATIONS AND USAGE
ADAGEN
® (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency
in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for – or who have failed – bone
marrow transplantation. ADAGEN
® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any
age at the time of diagnosis. ADAGEN
® (pegademase bovine) Injection is not intended as a replacement for HLA identical bone
marrow transplant therapy. ADAGEN
® (pegademase bovine) Injection is also not intended to replace continued close medical
supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gammaglobulin) as
indicated for intercurrent illnesses.
CONTRAINDICATIONS
There is no evidence to support the safety and efficacy of ADAGEN
® (pegademase bovine) Injection as preparatory or support
therapy for bone marrow transplantation. Since ADAGEN
® (pegademase bovine) Injection is administered by intramuscular injection,
it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.
PRECAUTIONS
General
Any laboratory or clinical indication of a decrease in potency of ADAGEN
® (pegademase bovine) Injection should be reported
immediately by telephone to Enzon Pharmaceuticals, Inc. Telephone 866-792-5172.
There have been no reports of hypersensitivity reactions in patients who have been treated with ADAGEN
® (pegademase bovine)
Injection.
One of 12 patients showed an enhanced rate of clearance of plasma ADA activity after 5 months of therapy at 15 U/kg/week.
Enhanced clearance was correlated with the appearance of an antibody that directly inhibited both unmodified ADA and ADAGEN
®
(pegademase bovine) Injection. Subsequently, the patient was treated with twice weekly intramuscular injections at an increased dose
of 20 U/kg, or a total weekly dose of 40 U/kg. No adverse effects were observed at the higher dose and effective levels of plasma
ADA were restored. After 4 months, the patient returned to a weekly dosage schedule of 20 U/kg and effective plasma levels have
been maintained.
Appropriate care to protect immune deficient patients should be maintained until improvement in immune function has been
documented. The degree of immune function improvement may vary from patient to patient and, therefore, each patient will require
appropriate care consistent with immunologic status.
Laboratory Tests
The treatment of SCID associated with ADA deficiency with ADAGEN
® (pegademase bovine) Injection should be monitored by
measuring plasma ADA activity and red blood cell dATP levels.
Plasma ADA activity and red cell dATP should be determined prior to treatment. Once treatment with ADAGEN
® (pegademase
bovine) Injection has been initiated, a desirable range of plasma ADA activity (trough level before maintenance injection) should be
15–35 µmol/hr/mL. This minimum trough level will ensure that plasma ADA activity from injection to injection is maintained above
the level of total erythrocyte ADA activity in the blood of normal individuals.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Plasma ADA activity (pre-injection) should be determined every 1-2 weeks during the first 8-12 weeks of treatment in order to
establish an effective dose of ADAGEN
® (pegademase bovine) Injection. After 2 months of maintenance treatment with ADAGEN
®
(pegademase bovine) Injection, red cell dATP levels should decrease to a range of ≤ 0.005 to 0.015 µmol/mL. The normal value of
dATP is below 0.001 µmol/mL. Once the level of dATP has fallen adequately, it should be measured 2-4 times a year during the
remainder of the first year and 2-3 times a year thereafter, assuming no interruption in therapy.
Between 3 and 9 months, plasma ADA should be determined twice a month, then monthly until after 18-24 months of treatment with
ADAGEN
® (pegademase bovine) Injection.
Patients who have successfully been maintained on therapy for two years should continue to have plasma ADA measured every 2-4
months and red cell dATP measured twice yearly. More frequent monitoring would be necessary if therapy were interrupted or if an
enhanced rate of clearance of plasma ADA activity develops.
Once effective ADA plasma levels have been established, should a patient’s plasma ADA activity level fall below 10 µmol/hr/mL
(which cannot be attributed to improper dosing, sample handling or antibody development) then the patient receiving this lot of
ADAGEN
® (pegademase bovine) Injection should be requested to have a blood sample for plasma ADA determination taken prior to
their next injection of ADAGEN
® (pegademase bovine) Injection.
Immune function, including the ability to produce antibodies, generally improves after 2-6 months of therapy, and matures over a
longer period. Compared with the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward
diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN
®
(pegademase bovine) Injection. However, the lag between the correction of the metabolic abnormalities and improved immune
function with a trend toward diminished frequency of infections and complications of infection is variable, and has ranged from a few
weeks to approximately 6 months. Improvement in the general clinical status of the patient may be gradual (as evidenced by
improvement in various clinical parameters) but should be apparent by the end of the first year of therapy. Antibody to ADAGEN
®
(pegademase bovine) Injection may develop in patients and may result in more rapid clearance of ADAGEN
® (pegademase bovine)
Injection. Antibody to ADAGEN
® (pegademase bovine) Injection should be suspected if a persistent fall in pre-injection levels of
plasma ADA to < 10 µmol/hr/mL occurs. If other causes for a decline in plasma ADA levels can be ruled out [such as improper
storage of ADAGEN
® (pegademase bovine) Injection vials (freezing or prolonged storage at temperatures above 8°C), or improper
handling of plasma samples (e.g., repeated freezing and thawing during transport to laboratory)], then a specific assay for antibody to
ADA and ADAGEN
® (pegademase bovine) Injection (ELISA, enzyme inhibition) should be performed.
In patients undergoing treatment with ADAGEN
® (pegademase bovine) Injection, a decline in immune function, with increased risk
of opportunistic infections and complications of infection, will result from failure to maintain adequate levels of plasma ADA activity
[whether due to the development of antibody to ADAGEN
® (pegademase bovine) Injection, to improper calculation of ADAGEN
®
(pegademase bovine) Injection dosage, to interruption of treatment or to improper storage of ADAGEN
® (pegademase bovine)
Injection with subsequent loss of activity]. If a persistent decline in plasma ADA activity occurs, immune function and clinical status
should be monitored closely and precautions should be taken to minimize the risk of infection. If antibody to ADA or ADAGEN
®
(pegademase bovine) Injection is found to be the cause of a persistent fall in plasma ADA activity, then adjustment in the dosage of
ADAGEN
® (pegademase bovine) Injection and other measures may be taken to induce tolerance and restore adequate ADA activity.
Drug Interactions
There are no known drug interactions with ADAGEN
® (pegademase bovine) Injection. However, Vidarabine is a substrate for ADA
and 2´-deoxycoformycin is a potent inhibitor of ADA. Thus, the activities of these drugs and ADAGEN
® (pegademase bovine)
Injection could be substantially altered if they are used in combination with one another.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenic studies in animals have not been performed with ADAGEN
® (pegademase bovine) Injection nor have studies
been performed on impairment of fertility.
ADAGEN
® (pegademase bovine) Injection did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in
the Ames assay.
Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with ADAGEN
® (pegademase bovine) Injection. It is
also not known whether ADAGEN
® (pegademase bovine) Injection can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. ADAGEN
® (pegademase bovine) Injection should be given to a pregnant woman only if clearly
needed.
Nursing Mothers
It is not known whether ADAGEN
® (pegademase bovine) Injection is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when ADAGEN
® (pegademase bovine) Injection is administered to a nursing woman.
ADVERSE REACTIONS
Clinical experience with ADAGEN
® (pegademase bovine) Injection has been limited. The following adverse reactions were reported
during clinical trials: headache in one patient and pain at the injection site in two patients.
The following adverse reactions have been identified during post-approval use of ADAGEN® (pegademase bovine) Injection.
Because these reactions are reported voluntarily from a very small population, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hematologic events: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia
Dermatological events: injection site erythema, urticaria
OVERDOSAGE
There is no documented experience with ADAGEN
® (pegademase bovine) Injection overdosage. An intraperitoneal dose of 50,000
U/kg of ADAGEN
® (pegademase bovine) Injection in mice resulted in weight loss up to 9%.
DOSAGE AND ADMINISTRATION
Before prescribing ADAGEN
® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this
prescribing information. For further information concerning the essential monitoring of ADAGEN
® (pegademase bovine) Injection
therapy, the prescribing physician should contact ENZON Pharmaceuticals, Inc., 685 Route 202/206, Bridgewater, NJ 08807.
Telephone 866-792-5172.
ADAGEN
® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of
diagnosis.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever
solution and container permits.
ADAGEN
® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.
ADAGEN
® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of
ADAGEN
® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose,
15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5
U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice
the upper limit of 35 µmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one
patient who received twice weekly injections (20 U/kg per dose) of ADAGEN
® (pegademase bovine) Injection. No adverse effects
have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 µmol/hr/mL
produces any additional clinical benefits.
Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. ADAGEN
®
(pegademase bovine) Injection is not recommended for intravenous administration.
The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA
activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP
content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual
patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before
maintenance injection) in the range of 15-35 µmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015
µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level,
as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any
patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with ADAGEN
®
(pegademase bovine) Injection.
HOW SUPPLIED
ADAGEN
® (pegademase bovine) Injection is a clear, colorless, preservative free solution for intramuscular injection. Each vial
contains 250 units/mL and is supplied as a 1.5 mL single-use vial, in boxes of 4 vials (NDC-57665-001-01).
Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.
Refrigerate. Store between +2°C and +8°C (36°F and 46°F). DO NOT FREEZE. ADAGEN
® (pegademase bovine) Injection should
not be stored at room temperature. This product should not be used if there are any indications that it may have been frozen.
REFERENCES
1. Hershfield MS, Buckley RH, Greenberg ML, et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-
modified adenosine deaminase. N Engl J Med 1987; 316:589-96.
2. Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar ST, Scudiery D, Berger M, Sorensen RU. Adenosine deaminase deficiency
with late onset of recurrent infections: response to treatment with polyethylene glycolmodified adenosine deaminase. J Pediatr
1988; 113:312-17.
3. Kredich NM, Hershfield MS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside
phosphorylase deficiency. 6th ed. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease.
New York: McGraw Hill, 1989; 1045-75.
4. Hirschhorn R. Inherited enzyme deficiencies and immunodeficiency: adenosine deaminase (ADA) and purine nucleoside
phosphorylase (PNP) deficiencies. Clin Immunol Immunopathol 1986; 40:157-65.
5. Hirschhorn R, Roegner-Maniscalco V, Kuritsky L, Rosen FS. Bone marrow transplantation only partially restores purine
metabolites to normal adenosine deaminase-deficient patients. J Clin Invest 1981; 68:1387-93.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Polmar AH, Stern RC, Schwartz AL, Wetzler EM, Chase PA, Hirschhorn R. Enzyme replacement therapy for adenosine
deaminase deficiency and severe combined immunodeficiency. N Engl J Med 1976; 295:1337-43.
7. Rubinstein A, Hirschhorn R, Sicklick M, Murphy RA. In vivo and in vitro effects of thymosin and adenosine deaminase on
adenosine-deaminase-deficient lymphocytes. N Engl J Med 1979; 300:387-92.
8. Hirschhorn R, Papageorgiou PS, Kesarwala HH, Taft LT. Amelioration of neurologic abnormalities after “enzyme replacement” in
adenosine deaminase deficiency. N Engl J Med 1980; 303:377-80.
9. Hirschhorn R, Ratech H, Rubinstein A, et al. Increased excretion of modified adenine nucleosides by children with adenosine
deaminase deficiency. Pediatr Res 1982; 16:362-9.
10. Polmar SH. Enzyme replacement and other biochemical approaches to the therapy of adenosine deaminase deficiency. In: Elliott
K, Whelan J, eds. Enzyme defects and immune dysfunction. Amsterdam: Excerpta Medica, 1979; 213-30.
© 1993-2008, ENZON Pharmaceuticals, Inc.
ENZON Pharmaceuticals, Inc.
Bridgewater, NJ 08807
All Rights Reserved
Issued February/2008
I-001-17-US-C
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019818s042lbl.pdf', 'application_number': 19818, 'submission_type': 'SUPPL ', 'submission_number': 42}
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NDA 19-821/S-002
NDA 19-821/S-006
Page 3
________________________________________________________________
Professional Package Insert
SORIATANE®
(acitretin)
CAPSULES
CAUSES BIRTH
DEFECTS
DO NOT
GET PREGNANT
CONTRAINDICATIONS AND WARNINGS: Soriatane must not be used by females who are pregnant,
or who intend to become pregnant during therapy or at any time for at least 3 years following
discontinuation of therapy. Soriatane also must not be used by females who may not use reliable
contraception while undergoing treatment or for at least 3 years following discontinuation of treatment.
Acitretin is a metabolite of etretinate (Tegison®), and major human fetal abnormalities have been reported
with the administration of acitretin and etretinate. Potentially, any fetus exposed can be affected.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 4
Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with
the formation of etretinate, which has a significantly longer elimination half-life than acitretin. Because
the longer elimination half-life of etretinate would increase the duration of teratogenic potential for
female patients, ethanol must not be ingested by female patients either during treatment with Soriatane or
for 2 months after cessation of therapy. This allows for elimination of acitretin, thus removing the
substrate for transesterification to etretinate. The mechanism of the metabolic process for conversion of
acitretin to etretinate has not been fully defined. It is not known whether substances other than ethanol are
associated with transesterification.
Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of
0.6, 3 and 15 mg/kg, respectively. These doses are approximately 0.2, 0.3 and 3 times the maximum
recommended therapeutic dose, respectively, based on a mg/m2 comparison.
Major human fetal abnormalities associated with acitretin and/or etretinate administration have been
reported including meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia,
syndactyly, absence of terminal phalanges, malformations of hip, ankle and forearm, low set ears, high
palate, decreased cranial volume, cardiovascular malformation and alterations of the skull and cervical
vertebrae.
Soriatane should be prescribed only by those who have special competence in the diagnosis and treatment
of severe psoriasis, are experienced in the use of systemic retinoids, and understand the risk of
teratogenicity.
Important Information for Women of Childbearing Potential:
Soriatane should be considered only for women with severe psoriasis
unresponsive to other therapies or whose clinical condition contraindicates the
use of other treatments.
Females of reproductive potential must not be given a prescription for Soriatane until pregnancy is
excluded. Soriatane is contraindicated in females of reproductive potential unless the patient meets ALL
of the following conditions:
•
Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL
before receiving the initial Soriatane prescription. The first test (a screening test) is obtained by the
prescriber when the decision is made to pursue Soriatane therapy. The second pregnancy test (a
confirmation test) should be done during the first 5 days of the menstrual period immediately
preceding the beginning of Soriatane therapy. For patients with amenorrhea, the second test should
be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective
forms of contraception [birth control] simultaneously). Timing of pregnancy testing throughout the
treatment course should be monthly or individualized based on the prescriber’s clinical judgment.
•
Must have selected and have committed to use 2 effective forms of contraception [birth control ]
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen
method, or the patient has undergone a hysterectomy or is clearly post menopausal.
•
Patients must use 2 effective forms of contraception [birth control] simultaneously for at least 1
month prior to initiation of Soriatane therapy, during Soriatane therapy, and for at least 3 years after
discontinuing Soriatane therapy. A Soriatane Patient Referral Form is available so that patients can
receive an initial free contraceptive counseling session and pregnancy testing. Counseling about
contraception and behaviors
associated with an increased risk of pregnancy must be repeated on a regular basis by the prescriber.
To encourage compliance with this recommendation, a limited supply of the drug should be
prescribed.
Effective forms of contraception include both primary and secondary forms
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of contraception. Primary forms of contraception include: tubal ligation,
partner’s vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products.
Secondary forms of contraception include diaphragms, latex condoms, and
cervical caps; each secondary form must be used with a spermicide.
Any birth control method can fail. Therefore, it is critically important that
women of childbearing potential use 2 effective forms of contraception [birth
control] simultaneously. It has not been established if there is a
pharmacokinetic interaction between acitretin and combined oral
contraceptives. However, it has been established that acitretin interferes
with the contraceptive effect of microdosed progestin preparations.2
Microdosed “minipill” progestin preparations are not recommended for use
with Soriatane. It is not known whether other progestational contraceptives,
such as implants and injectables, are adequate methods of contraception
during acitretin therapy.
Prescribers are advised to consult the package insert of any medication administered concomitantly
with hormonal contraceptives, since some medications may decrease the effectiveness of these birth
control products. Patients should be prospectively cautioned not to self-medicate with the herbal
supplement St. John’s Wort because a possible interaction has been suggested with hormonal
contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting
St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who
also used some form of St. John's Wort (see PRECAUTIONS).
•
Must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings
about the risk of potential birth defects if the fetus is exposed to Soriatane, about contraceptive
failure, and about the fact that they must not ingest beverages or products containing ethanol while
taking Soriatane and for 2 months after Soriatane treatment has been discontinued.
If pregnancy does occur during Soriatane therapy or at any time for at least 3 years following
discontinuation of Soriatane therapy, the prescriber and patient should discuss the possible effects on the
pregnancy. The available information is as follows:
Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy.
The risk of severe fetal malformations is well established when systemic retinoids are taken during
pregnancy. Pregnancy must also be prevented after stopping acitretin therapy, while the drug is being
eliminated to below a threshold blood concentration that would be associated with an increased
incidence of birth defects. Because this threshold has not been established for acitretin in humans and
because elimination rates vary among patients, the duration of posttherapy contraception to achieve
adequate elimination cannot be calculated precisely. It is strongly recommended that contraception
be continued for at least 3 years after stopping treatment with acitretin, based on the following
considerations:
♦ In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be
eliminated within 2 months, assuming a mean elimination half-life of 49 hours.
♦ In cases where etretinate is formed, as has been demonstrated with concomitant administration
of acitretin and ethanol,
•
greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a mean
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elimination half-life of 120 days.
•
greater than 98% of the etretinate formed would be eliminated in 3 years, based on the
longest demonstrated elimination half-life of 168 days.
However, etretinate was found in plasma and subcutaneous fat in one patient reported to have
had sporadic alcohol intake, 52 months after she stopped acitretin therapy.1
♦ Severe birth defects have been reported where conception occurred during the time interval when the
patient was being treated with acitretin and/or etretinate. In addition, severe birth defects have also
been reported when conception occurred after the mother completed therapy. These cases have been
reported both prospectively (before the outcome was known) and retrospectively (after the outcome
was known). The events below are listed without distinction as to whether the reported birth defects
are consistent with retinoid-induced embryopathy or not.
•
There have been 318 prospectively reported cases involving pregnancies and the use of
etretinate, acitretin or both. In 238 of these cases, the conception occurred after the last dose of
etretinate (103 cases), acitretin (126) or both (9). Fetal outcome remained unknown in
approximately one-half of these cases, of which 62 were terminated and 14 were spontaneous
abortions. Fetal outcome is known for the other 118 cases and 15 of the outcomes were
abnormal (including cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia,
hypotonia, limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental
disorder/death, undescended testicle and 5 cases of premature birth). In the 126 prospectively
reported cases where conception occurred after the last dose of acitretin only, 43 cases involved
conception at least 1 year but less than 2 years after the last dose. There were 3 reports of
abnormal outcomes out of these 43 cases (involving limb malformation, GI tract malformations
and premature birth). There were only 4 cases where conception occurred at least 2 years after
the last dose but there were no reports of birth defects in these cases.
•
There are also a total of 35 retrospectively reported cases where conception occurred at least one
year after the last dose of etretinate, acitretin or both. From these cases there are 3 reports of
birth defects when the conception occurred at least 1 year but less than 2 years after the last dose
of acitretin (including heart malformations, Turner's Syndrome, and unspecified congenital
malformations) and 4 reports of birth defects when conception occurred 2 or more years after the
last dose of acitretin (including foot malformation, cardiac malformations [2 cases] and
unspecified neonatal and infancy disorder). There were 3 additional abnormal outcomes in cases
where conception occurred 2 or more years after the last dose of etretinate (including
chromosome disorder, forearm aplasia and stillbirth.
•
Females who have taken Tegison (etretinate) must continue to follow the contraceptive
recommendations for Tegison. Tegison is no longer marketed in the U.S.; for information, call
Roche at 1-800-526-6367.
•
Patients should not donate blood during and for at least 3 years following the completion of
Soriatane therapy because women of childbearing potential must not receive blood from patients
being treated with Soriatane.
Important Information For Males Taking Soriatane:
♦ Patients should not donate blood during and for at least 3 years following
Soriatane therapy because women of childbearing potential must not
receive blood from patients being treated with Soriatane.
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♦ Samples of seminal fluid from 3 male patients treated with acitretin and 6
male patients treated with etretinate have been assayed for the presence of
acitretin. The maximum concentration of acitretin observed in the seminal
fluid of these men was 12.5 ng/mL. Assuming an ejaculate volume of 10 mL,
the amount of drug transferred in semen would be 125 ng, which is
1/200,000 of a single 25 mg capsule. Thus, although it appears that residual
acitretin in seminal fluid poses little, if any, risk to a fetus while a male
patient is taking the drug or after it is discontinued, the no-effect limit for
teratogenicity is unknown and there is no registry for birth defects
associated with acitretin. The available data are as follows:
There have been 25 cases of reported conception when the male partner
was taking acitretin. The pregnancy outcome is known in 13 of these 25
cases. Of these, 9 reports were retrospective and 4 were prospective
(meaning the pregnancy was reported prior to knowledge of the
outcome):
NOTE to HLR: I had technical difficulties inserting the data table here that is
based on your Dermatology 2002 paper. Please insert here exactly as in the
approval letter. Please also insert the reference for the data and adjust
reference numbers that follow in the labeling accordingly)
For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT
EACH TIME SORIATANE IS DISPENSED, AS REQUIRED BY LAW.
DESCRIPTION: Soriatane (acitretin), a retinoid, is available in 10 mg and 25 mg gelatin capsules for oral administration.
Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a
metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder
with a molecular weight of 326.44. The structural formula is:
[[graphic: molecular structure]]
Each capsule contains acitretin, microcrystalline cellulose, sodium ascorbate, gelatin, black monogramming ink and
maltodextrin (a mixture of polysaccharides).
Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide. They may also contain
benzyl alcohol, carboxymethylcellulose sodium, edetate calcium disodium.
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CLINICAL PHARMACOLOGY: The mechanism of action of Soriatane is unknown.
Pharmacokinetics: Absorption: Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was
given with food in all of the following studies. After administration of a single 50 mg oral dose of acitretin to 18 healthy
subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean 416 ng/mL) and were achieved in 2 to 5
hours (mean 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg.
Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was
given to 12 healthy subjects.
Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism (see Pharmacokinetic Drug Interactions: Ethanol): Following oral absorption, acitretin undergoes extensive
metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin
relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent
compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are
excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in
plasma are achieved within approximately 3 weeks.
Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the
feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose
administration is 49 hours (range 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range 28
to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
Special Populations: Psoriasis: In an 8-week study of acitretin pharmacokinetics in patients with psoriasis, mean steady-
state trough concentrations of acitretin increased in a dose proportional manner with dosages ranging from 10 to 50 mg
daily. Acitretin plasma concentrations were nonmeasurable (<4 ng/mL) in all patients 3 weeks after cessation of therapy.
Elderly: In a multiple-dose study in healthy young (n=6) and elderly (n=8) subjects, a two-fold increase in acitretin plasma
concentrations were seen in elderly subjects, although the elimination half-life did not change.
Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in end-stage renal failure subjects (n=6)
when compared to age-matched controls, following single 50 mg oral doses. Acitretin was not removed by hemodialysis in
these subjects.
Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS:
Drug Interactions): In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and
cimetidine, digoxin, phenprocoumon or glyburide.
Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed
with concurrent ingestion of acitretin and ethanol. In a two-way crossover study, all 10 subjects formed etretinate with
concurrent ingestion of a single 100 mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol,
approximately 1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range 22 to 105 ng/mL) was
observed, and extrapolation of AUC values indicated that the formation of etretinate in this study was comparable to a
single 5 mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100 mg oral dose of
acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent
ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93 evaluable psoriatic
patients on acitretin therapy in several foreign studies (10 to 80 mg/day), 16% had measurable etretinate levels (>5 ng/mL).
Etretinate has a much longer elimination half-life compared to that of acitretin. In one study the apparent mean terminal
half-life after 6 months of therapy was approximately 120 days (range 84 to 168 days). In another study of 47 patients
treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years
after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.
Progestin-only Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and
combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of
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microdosed progestin preparations.2 Microdosed “minipill” progestin preparations are not recommended for use with
Soriatane. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate
methods of contraception during acitretin therapy.
CLINICAL STUDIES: In two double-blind placebo controlled studies, Soriatane was administered once daily to patients
with severe psoriasis (ie, covering at least 10% to 20% of the body surface area). At 8 weeks (see Table 1) patients treated
in Study A with 50 mg Soriatane per day showed significant improvements (p ≤ 0.05) relative to baseline and to placebo in
the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In
study B, differences from baseline and from placebo were statistically significant (p ≤ 0.05) for all variables at both the 25
mg and 50 mg doses; it should be noted for Study B that no statistical adjustment for multiplicity was carried out.
Table 1.
Summary of the Soriatane Efficacy Results of the 8-Week
Double-Blind Phase of Studies A and B
Study A
Study B
Total daily dose
Total daily dose
Efficacy Variables
Placebo
(N=29)
50 mg
(N=29)
Placebo
(N=72)
25 mg
(N=74)
50 mg
(N=71)
Physician’s Global
Evaluation
Baseline
4.62
4.55
4.43
4.37
4.49
Mean Change After 8
Weeks
-0.29
-2.00*
-0.06
-1.06*
-1.57*
Scaling
Baseline
4.10
3.76
3.97
4.11
4.10
Mean Change After 8
Weeks
-0.22
-1.62*
-0.21
-1.50*
-1.78*
Thickness
Baseline
4.10
4.10
4.03
4.11
4.20
Mean Change After 8
Weeks
-0.39
-2.10*
-0.18
-1.43*
-2.11*
Erythema
Baseline
4.21
4.59
4.42
4.24
4.45
Mean Change After 8
Weeks
-0.33
-2.10*
-0.37
-1.12*
-1.65*
*Values were statistically significantly different from placebo and from baseline (p ≤ 0.05). No
adjustment for multiplicity was done for Study B.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema,
and the physician’s global evaluation of the current status of the disease. Ratings of scaling,
erythema, and lesion thickness, and the ratings of the global assessments were made using a
seven-point scale (0=none, 1=trace, 2=mild, 3=mild-moderate, 4=moderate, 5=moderate-severe,
6=severe).
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A subset of 141 patients from both pivotal studies A and B continued to receive Soriatane in
an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables,
as indicated in Table 2, were significantly improved (p ≤ 0.01) from baseline, including extent
of psoriasis, mean ratings of psoriasis severity and physician’s global evaluation.
Table 2. Summary of the First Course of Soriatane Therapy
(24 Weeks)
Variables
Study A
Study B
Mean Total Daily Soriatane Dose
(mg)
42.8
43.1
Mean Duration of Therapy (Weeks)
21.1
22.6
Physician’s Global Evaluation
Baseline
Mean Change From Baseline
N=39
4.51
-2.26*
N=98
4.43
-2.60*
Scaling
Baseline
Mean Change From Baseline
N=59
3.97
-2.15 *
N=132
4.07
-2.42*
Thickness
Baseline
Mean Change From Baseline
N=59
4.00
-2.44*
N=132
4.12
-2.66*
Erythema
Baseline
Mean Change From Baseline
N=59
4.35
-2.31*
N=132
4.33
-2.29*
*Indicates that the difference from baseline was statistically significant (p ≤ 0.01).
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema; and the
physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion
thickness, and the ratings of the global assessments were made using a seven-point scale (0=none, 1=trace,
2=mild, 3=mild-moderate, 4=moderate, 5=moderate-severe, 6=severe).
All efficacy variables improved significantly in a subset of 55 patients from Study A treated for a second, 6-month
maintenance course of therapy (for a total of 12 months of treatment); a small subset of patients (n=4) from Study A
continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).
INDICATIONS AND USAGE: Soriatane is indicated for the treatment of severe psoriasis in adults. Because of
significant adverse effects associated with its use, Soriatane should be prescribed only by those knowledgeable in the
systemic use of retinoids. In females of reproductive potential, Soriatane should be reserved for non-pregnant patients who
are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see Boxed
CONTRAINDICATIONS AND WARNING: Soriatane can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated,
have produced efficacy results similar to the initial course of therapy.
CONTRAINDICATIONS: Pregnancy Category X (see boxed CONTRAINDICATIONS AND WARNINGS).
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Soriatane is contraindicated in patients with severely impaired liver or kidney function and in patients with chronic
abnormally elevated blood lipid values (see boxed WARNINGS, Hepatotoxicity; WARNINGS, Lipids; and
PRECAUTIONS).
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate.] Consequently,
the combination of methotrexate with Soriatane is also contraindicated (see PRECAUTIONS: Drug Interactions).
Since both Soriatane and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see
WARNINGS: Pseudotumor Cerebri).
Soriatane is contraindicated in cases of hypersensitivity to the preparation (acitretin or
excipients) or to other retinoids.
WARNINGS: (See also boxed CONTRAINDICATIONS AND WARNINGS)
Hepatotoxicity: Of the 525 patients treated in US clinical trials, 2 had clinical jaundice with elevated serum
bilirubin and transaminases considered related to Soriatane treatment. Liver function test results in these patients
returned to normal after Soriatane was discontinued. Two of the 1289 patients treated in European clinical trials
developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these patients revealed nodule formation
suggestive of cirrhosis. One patient in a Canadian clinical trial of 63 patients developed a three-fold increase of
transaminases. A liver biopsy of this patient showed mild lobular disarray, multifocal hepatocyte loss and mild
triaditis of the portal tracts compatible with acute reversible hepatic injury. The patient's transaminase levels
returned to normal 2 months after Soriatane was discontinued.
The potential of Soriatane therapy to induce hepatotoxicity was prospectively evaluated using liver biopsies in an
open-label study of 128 patients. Pretreatment and posttreatment biopsies were available for 87 patients. A
comparison of liver biopsy findings before and after therapy revealed 49 (58%) patients showed no change, 21
(25%) improved and 14 (17%) patients had a worsening of their liver biopsy status. For 6 patients, the
classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and
portal inflammation; both mild); for 7 patients, the change was from class I to class II (fatty infiltration, nuclear
variability, portal inflammation and focal necrosis; all moderate to severe); and for 1 patient, the change was from
class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test
result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found.
Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP) or LDH have occurred in approximately 1 in 3 patients
treated with Soriatane. Of the 525 patients treated in clinical trials in the US, treatment was discontinued in 20
(3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with Soriatane,
the drug should be discontinued and the etiology further investigated.
Ten of 652 patients treated in US clinical trials of etretinate, of which acitretin is the
active metabolite, had clinical or histologic hepatitis considered to be possibly or
probably related to etretinate treatment. There have been reports of hepatitis-related
deaths worldwide; a few of these patients had received etretinate for a month or less
before presenting with hepatic symptoms or signs.
Hyperostosis: In adults receiving long-term treatment with Soriatane, appropriate
examinations should be periodically performed in view of possible ossification abnormalities
(see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic bony
abnormality in adults is low, periodic radiography is only warranted in the presence of
symptoms or long term use of Soriatane. If such disorders arise, the continuation of therapy
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should be discussed with the patient on the basis of a careful risk/benefit analysis. In clinical
trials with Soriatane, patients were prospectively evaluated for evidence of development or
change in bony abnormalities of the vertebral column, knees and ankles.
Vertebral Results: Of 380 patients treated with Soriatane, 15% had preexisting abnormalities
of the spine which showed new changes or progression of preexisting findings. Changes
included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal
hyperostosis, ligament calcification and narrowing and destruction of a cervical disc space.
De novo changes (formation of small spurs) were seen in 3 patients after 1½ to 2½ years.
Skeletal Appendicular Results: Six of 128 patients treated with Soriatane showed abnormalities in the knees and ankles
before treatment that progressed during treatment. In 5, these changes involved the formation of additional spurs or
enlargement of existing spurs. The sixth patient had degenerative joint disease which worsened. No patients developed
spurs de novo. Clinical complaints did not predict radiographic changes.
Lipids and Possible Cardiovascular Effects: Blood lipid determinations should be performed before Soriatane is
administered and again at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8
weeks. In patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of patients. These effects of
Soriatane were generally reversible upon cessation of therapy.
Patients with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism,
diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions. Because of the risk of
hypertriglyceridemia, serum lipids must be more closely monitored in high-risk patients and during long-term treatment.
Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status.
Although no causal relationship has been established, there have been post-marketing
reports of acute myocardial infarction or thromboembolic events in patients on Soriatane
therapy. In addition, elevation of serum triglycerides to greater than 800 mg/dL has been
associated with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in
Soriatane dose, or drug therapy should be employed to control significant elevations of
triglycerides. If, despite these measures, hypertriglyceridemia and low HDL levels persist, the
discontinuation of Soriatane should be considered.
Ophthalmologic Effects: The eyes and vision of 329 patients treated with Soriatane were examined by ophthalmologists.
The findings included dry eyes (23%), irritation of eyes (9%) and brow and lash loss (5%). The following were reported in
less than 5% of patients: Bell's Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial
abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear cataract, pannus, papilledema,
photophobia, posterior subcapsular cataract, recurrent sties and subepithelial corneal lesions.
Any patient treated with Soriatane who is experiencing visual difficulties should discontinue
the drug and undergo ophthalmologic evaluation.
Pancreatitis: Lipid elevations occur in 25% to 50% of patients treated with Soriatane. Triglyceride increases sufficient to
be associated with pancreatitis are much less common, although fatal fulminant pancreatitis has been reported. There have
been rare reports of pancreatitis during Soriatane therapy in the absence of hypertrigyceridemia.
Pseudotumor Cerebri: Soriatane and other retinoids administered orally have been associated with cases of pseudotumor
cerebri (benign intracranial hypertension). Some of these events involved concomitant use of isotretinoin and tetracyclines.
However, the event seen in a single Soriatane patient was not associated with tetracyline use. Early signs and symptoms
include papilledema, headache, nausea and vomiting and visual disturbances. Patients with these signs and symptoms
should be examined for papilledema and, if present, should discontinue Soriatane immediately and be referred for
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neurological evaluation and care. Since both Soriatane and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see CONTRAINDICATIONS).
PRECAUTIONS: Information for Patients (see Medication Guide for all patients and Patient Agreement/Informed
Consent for Female Patients at end of professional labeling):
Patients should be instructed to read the Medication Guide supplied as required by law when Soriatane is dispensed.
Females of reproductive potential: Soriatane can cause severe birth defects. Female
patients must not be pregnant when Soriatane therapy is initiated, they must not become
pregnant while taking Soriatane, and for at least 3 years after stopping Soriatane so that
the drug can be eliminated to below a blood concentration that would be associated with
an increased incidence of birth defects. Because this threshold has not been established
for acitretin in humans and because elimination rates vary among patients, the duration of
posttherapy contraception to achieve adequate elimination cannot be calculated precisely
(see boxed CONTRAINDICATIONS AND WARNINGS).
Females of reproductive potential should also be advised that they must not ingest
beverages or products containing ethanol while taking Soriatane and for 2 months
after Soriatane treatment has been discontinued. This allows for elimination of the
acitretin which can be converted to etretinate in the presence of alcohol.
Female patients should be advised that any method of birth control can fail, including tubal ligation, and that microdosed
progestin “minipill” preparations are not recommended for use with Soriatane. Data from one patient who received a
very low-dosed progestin contraceptive (levonorgestrel 0.03 mg) had a significant increase of the progesterone level
after three menstrual cycles during acitretin treatment.2
Female patients should sign a consent form prior to beginning Soriatane therapy (see boxed CONTRAINDICATIONS
AND WARNINGS).
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective
case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive
Soriatane prior to or during nursing because of the potential for serious adverse reactions in nursing infants.
All Patients:
Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have been
reported. These events, including self-injurious behavior, have been reported in patients taking other systemically
administered retinoids, as well as in patients taking Soriatane. Since other factors may have contributed to these events, it is
not known if they are related to Soriatane. Patients should be counseled to stop taking Soriatane and notify their prescriber
immediately if they experience psychiatric symptoms.
Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period.
Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of Soriatane, although
some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials.
Decreased night vision has been reported with Soriatane therapy. Patients should be
advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night. Visual problems should be carefully monitored (see WARNINGS and
ADVERSE REACTIONS). Patients should be advised that they may experience decreased
tolerance to contact lenses during the treatment period and sometimes after treatment has
stopped.
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Patients should not donate blood during and for at least 3 years following therapy because Soriatane can cause birth defects
and women of childbearing potential must not receive blood from patients being treated with Soriatane.
Because of the relationship of Soriatane to vitamin A, patients should be advised against taking vitamin A supplements in
excess of minimum recommended daily allowances to avoid possible additive toxic effects.
Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the
effects of UV light are enhanced by retinoids.
Patients should be advised that they must not give their Soriatane capsules to any other
person.
For Prescribers:
Phototherapy: Significantly lower doses of phototherapy are required when Soriatane is used because Soriatane-induced
effects on the stratum corneum can increase the risk of erythema (burning). (see DOSAGE AND ADMINISTRATION).
Drug Interactions:
Ethanol: Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see
boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Glibenclamide: In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of
glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male
volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of
diabetic patients under treatment with Soriatane is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics
and DOSAGE AND ADMINISTRATION).
Hormonal Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and
combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of
microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use
with Soriatane. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate
methods of contraception during acitretin therapy.
Methotrexate: An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate.
Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS).
Phenytoin: If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.
Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is
contraindicated (see CONTRAINDICATIONS AND WARNINGS: Pseudotumor Cerebri).
Vitamin A and oral retinoids: Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be
avoided because of the risk of hypervitaminosis A.
Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine,
digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of
anticoagulants of the coumarin type (warfarin) revealed no interaction.
Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring
or treatment discontinuation is recommended, depending on clinical judgment.
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Blood Sugar: Some patients receiving retinoids have experienced problems with blood sugar control. In addition, new
cases of diabetes have been diagnosed during retinoid therapy, including diabetic ketoacidosis. In diabetics, blood-sugar
levels should be monitored very carefully.
Lipids: In clinical studies, the incidence of hypertriglyceridemia was 66%, hypercholesterolemia was 33% and that of
decreased HDL was 40%. Pretreatment and follow-up measurements should be obtained under fasting conditions. It is
recommended that these tests be performed weekly or every other week until the lipid response to Soriatane has
stabilized (see WARNINGS).
Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3
patients treated with Soriatane. It is recommended that these tests be performed prior to initiation of Soriatane therapy, at
1- to 2-week intervals until stable and thereafter at intervals as clinically indicated (see CONTRAINDICATIONS AND
boxed WARNING).
Carcinogenesis, Mutagenesis and Impairment of Fertility: Carcinogenesis: A carcinogenesis study of acitretin in Wistar
rats, at doses up to 2 mg/kg/day administered 7 days/week for 104 weeks, has been completed. There were no neoplastic
lesions observed that were considered to have been related to treatment with acitretin. An 80 week carcinogenesis study in
mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study
demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all
times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas
at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum
recommended human therapeutic dose based on a mg/m2 comparison.
Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT)
assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts and in an in vivo mouse
micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.
Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not
impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the
maximum recommended therapeutic dose based on a mg/m2 comparison). Chronic toxicity
studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic
arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30
mg/kg/day).
No decreases in sperm count or concentration and no changes in sperm motility or
morphology were noted in 31 men (17 psoriatic patients, 8 patients with disorders of
keratinization and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12
weeks. In these studies, no deleterious effects were seen on either testosterone production,
LH or FSH in any of the 31 men.3-5 No deleterious effects were seen on the hypothalamic-
pituitary axis in any of the 18 men where it was measured.3,4
Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed CONTRAINDICATIONS AND WARNINGS).
In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for 10 weeks (approximate
duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were
observed in the progeny. (see boxed CONTRAINDICATIONS AND WARNINGS for information about male use of
Soriatane.)
Nonteratogenic Effects: In rats dosed at 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose
based on a mg/m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest
dose tested, 1 mg/kg/day, no treatment-related adverse effects were observed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No clinical studies have been
conducted in pediatric patients. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses,
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decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic
retinoids, including etretinate, a metabolite of Soriatane. A causal relationship between these effects and Soriatane has not
been established. While it is not known that these occurrences are more severe or more frequent in children, there is special
concern in pediatric patients because of the implications for growth potential (see WARNINGS: Hyperostosis).
Geriatric Use: Clinical studies of Soriatane did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy. A two-fold increase in acitretin plasma concentrations was seen
in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL
PHARMACOLOGY: Special Populations).
ADVERSE REACTIONS: Hypervitaminosis A produces a wide spectrum of signs and
symptoms primarily of the mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and
central nervous systems. Many of the clinical adverse reactions reported to date with
Soriatane administration resemble those of the hypervitaminosis A syndrome.
Adverse Events/Post-Marketing Reports: In addition to the events listed in the tables for the clinical trials, the following
adverse events have been identified during post-approval use of Soriatane. Because these events are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism, (see WARNINGS), stroke
Nervous System: Myopathy with peripheral neuropathy has been reported during Soriatane
therapy. Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events, including self-injurious
behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking
Soriatane. Since other factors may have contributed to these events, it is not known if they are related to Soriatane (see
PRECAUTIONS).
Reproductive: Vulvo-vaginitis due to Candida albicans
Skin and Appendages: Thinning of the skin, skin fragility and scaling may occur all over the body, particularly on the palms
and soles; nail fragility is frequently observed.
Clinical Trials: During clinical trials with Soriatane, 513/525 (98%) of patients reported a total
of 3545 adverse events. One-hundred sixteen patients (22%) left studies prematurely,
primarily because of adverse experiences involving the mucous membranes and skin. Three
patients died. Two of the deaths were not drug related (pancreatic adenocarcinoma and lung
cancer); the other patient died of an acute myocardial infarction, considered remotely related
to drug therapy. In clinical trials, Soriatane was associated with elevations in liver function test
results or triglyceride levels and hepatitis.
The tables below list by body system and frequency the adverse events reported during
clinical trials of 525 patients with psoriasis.
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Table 3. Adverse Events Frequently Reported During Clinical Trials
Percent of Patients Reporting (N=525)
BODY SYSTEM
>75%
50% to 75%
25% to 50%
10% to 25%
CNS
Rigors
Eye Disorders
Xerophthalmia
Mucous Membranes
Cheilitis
Rhinitis
Dry mouth
Epistaxis
Musculoskeletal
Arthralgia
Spinal hyperostosis
(progression of
existing lesions)
Skin and Appendages
Alopecia
Skin peeling
Dry skin
Nail disorder
Pruritus
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Table 4. Adverse Events Less Frequently Reported During Clinical Trials
(Some of Which May Bear No Relationship to Therapy)
Percent of Patients Reporting (N=525)
BODY SYSTEM
1% to 10%
<1%
Body as a Whole
Anorexia
Edema
Fatigue
Hot flashes
Increased appetite
Alcohol intolerance
Dizziness
Fever
Influenza-like symptoms
Malaise
Moniliasis
Muscle weakness
Weight increase
Cardiovascular
Flushing
Chest pain
Cyanosis
Increased bleeding time
Intermittent claudication
Peripheral ischemia
CNS
(also see Psychiatric)
Headache
Pain
Abnormal gait
Migraine
Neuritis
Pseudotumor cerebri (intracranial
hypertension)
Eye Disorders
Abnormal/blurred vision
Blepharitis
Conjunctivitis/irritation
Corneal epithelial abnormality
Decreased night vision/night
blindness
Eye abnormality
Eye pain
Photophobia
Abnormal lacrimation
Chalazion
Conjunctival hemorrhage
Corneal ulceration
Diplopia
Ectropion
Itchy eyes and lids
Papilledema
Recurrent sties
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BODY SYSTEM
1% to 10%
<1%
Subepithelial corneal lesions
Gastrointestinal
Abdominal pain
Diarrhea
Nausea
Tongue disorder
Constipation
Dyspepsia
Esophagitis
Gastritis
Gastroenteritis
Glossitis
Hemorrhoids
Melena
Tenesmus
Tongue ulceration
Liver and Biliary
Hepatic function abnormal
Hepatitis
Jaundice
Mucous Membranes
Gingival bleeding
Gingivitis
Increased saliva
Stomatitis
Thirst
Ulcerative stomatitis
Altered saliva
Anal disorder
Gum hyperplasia
Hemorrhage
Pharyngitis
Musculoskeletal
Arthritis
Arthrosis
Back pain
Hypertonia
Myalgia
Osteodynia
Peripheral joint Hyperostosis
(progression of existing
lesions)
Bone disorder
Olecranon bursitis
Spinal hyperostosis (new lesions)
Tendonitis
Psychiatric
Depression
Insomnia
Somnolence
Anxiety
Dysphonia
Libido decreased
Nervousness
Reproductive
Atrophic vaginitis
Leukorrhea
Respiratory
Sinusitis
Coughing
Increased sputum
Laryngitis
Skin and Appendages
Abnormal skin odor
Abnormal hair texture
Bullous eruption
Cold/clammy skin
Dermatitis
Increased sweating
Infection
Psoriasiform rash
Purpura
Pyogenic granuloma
Rash
Seborrhea
Skin fissures
Skin ulceration
Sunburn
Acne
Breast pain
Cyst
Eczema
Fungal infection
Furunculosis
Hair discoloration
Herpes simplex
Hyperkeratosis
Hypertrichosis
Hypoesthesia
Impaired healing
Otitis media
Otitis externa
Photosensitivity reaction
Psoriasis aggravated
Scleroderma
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BODY SYSTEM
1% to 10%
<1%
Skin nodule
Skin hypertrophy
Skin disorder
Skin irritation
Sweat gland disorder
Urticaria
Verrucae
Special Senses/Other
Earache
Taste perversion
Tinnitus
Ceruminosis
Deafness
Taste loss
Urinary
Abnormal urine
Dysuria
Penis disorder
Laboratory: Soriatane therapy induces changes in liver function tests in a significant number of patients. Elevations of AST
(SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 patients treated with Soriatane. In most patients,
elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of
treatment. In patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient,
usually reversible elevations of alkaline phosphatase have been observed.
Table 5 lists the laboratory abnormalities reported during clinical trials.
Table 5. Abnormal Laboratory Test Results Reported During Clinical Trials
Percent of Patients Reporting
BODY SYSTEM
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Electrolytes
Increased:
– Phosphorus
– Potassium
– Sodium
Increased and
decreased
magnesium
Decreased:
– Phosphorus
– Potassium
– Sodium
Increased and
decreased:
– Calcium
– Chloride
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Hematologic
Increased
-Reticulocytes
Decreased:
– Hematocrit
– Hemoglobin
– WBC
Increased:
– Haptoglobin
– Neutrophils
– WBC
Increased:
– Bands
– Basophils
– Eosinophils
– Hematocrit
– Hemoglobin
– Lymphocytes
– Monocytes
Decreased:
– Haptoglobin
– Lymphocytes
– Neutrophils
– Reticulocytes
Increased or
decreased:
– Platelets
– RBC
Hepatic
Increased:
– Cholesterol
– LDH
– SGOT
– SGPT
Decreased:
– HDL cholesterol
Increased:
– Alkaline
phosphatase
– Direct bilirubin
– GGTP
Increased:
– Globulin
– Total bilirubin
– Total protein
Increased and
decreased:
– Serum albumin
Miscellaneous
Increased
triglycerides
Increased:
– CPK
– Fasting blood
sugar
Decreased:
– Fasting blood
sugar
– High occult
blood
Increased and
decreased:
– Iron
Renal
Increased:
– Uric acid
Increased:
– BUN
– Creatinine
Urinary
WBC in urine
Acetonuria
Hematuria
RBC in urine
Glycosuria
Proteinuria
OVERDOSAGE: In the event of acute overdosage, Soriatane must be withdrawn at once. Symptoms of overdose are
identical to acute hypervitaminosis A, ie, headache and vertigo. The acute oral toxicity (LD50) of acitretin in both mice and
rats was greater than 4000 mg/kg.
In one reported case of overdose, a 32-year-old male with Darier's disease took 21 x 25 mg capsules (525 mg single dose).
He vomited several hours later but experienced no other ill effects.
All female patients of childbearing potential who have taken an overdose of Soriatane must: 1) Have a pregnancy test at the
time of overdose. 2) Be counseled as per the boxed Contraindications and Warnings and Precautions sections regarding
birth defects and contraceptive use for at least 3 years duration after the overdose.
DOSAGE AND ADMINISTRATION: There is intersubject variation in the pharmacokinetics, clinical efficacy and
incidence of side effects with Soriatane. A number of the more common side effects are dose related. Individualization of
dosage is required to achieve sufficient therapeutic response while minimizing side effects. Soriatane therapy should be
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initiated at 25 to 50 mg per day, given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may
be given dependent upon an individual patient's response to initial treatment. Relapses may be treated as outlined for initial
therapy.
When Soriatane is used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s
individual response (see PRECAUTIONS: General).
Females who have taken Tegison (etretinate) must continue to follow the contraceptive recommendations for
Tegison.
Information for Pharmacists: A Soriatane Medication Guide must be given to the patient each time Soriatane is dispensed,
as required by law.
HOW SUPPLIED: Brown and white capsules, 10 mg, imprinted SORIATANE 10 ROCHE; bottles of 30 (NDC 0004-
0288-57).
Brown and yellow capsules, 25 mg, imprinted SORIATANE 25 ROCHE; bottles of 30 (NDC 0004-0289-57).
Store between 15o and 25oC (59o and 77oF). Protect from light. Avoid exposure to high temperatures and humidity after the
bottle is opened.
1. REFERENCES: Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389.
2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after long-term acitretin. Lancet
348:1107, 1996.
3. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica
175:48-49, 1987.
4. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670).
Andrologia 22:479-482, 1990
5. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin.
In: Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3,
pp 253-254, 1988.
PATIENT AGREEMENT/INFORMED CONSENT for FEMALE Patients:
To be completed by the patient, her parent/guardian*and signed by her prescriber.
Read each item below and initial in the space provided to show that you understand each item and agree to follow your
doctor's instructions. Do not sign this consent and do not take Soriatane if there is anything that you do not
understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.
____________________________________________________________
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I am pregnant or become
pregnant while taking Soriatane in any amount even for short periods of time. Birth defects have also happened in babies of
women who became pregnant after stopping Soriatane treatment.
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2. I understand that I must not take Soriatane if I am pregnant.
Initial: ______
3. I understand that I must not become pregnant while taking Soriatane and for at least 3 years after the end of my treatment
with Soriatane.
Initial: ______
4. I know that I must avoid drinks, food, and medicines, including over-the-counter products, that contain alcohol. This is
extremely important, because alcohol changes Soriatane in the blood into a drug that takes even longer to leave the body.
This means the risk of birth defects may last longer than 3 years if I swallow any form of alcohol during Soriatane therapy
or for 2 months after I stop taking Soriatane.
5. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective forms of birth control
(contraception) at the same time. The only exception is if I have had surgery to remove the womb (a hysterectomy) or my
prescriber has told me I have gone completely through menopause.
Initial: ________
6. I have been told by my prescriber that 2 effective forms of birth control (contraception) must be used at the same time for
at least 1 month before starting Soriatane, for the entire time of Soriatane therapy, and for at least 3 years after Soriatane
treatment has stopped.
7. I understand that birth control pills and injectable/implantable/insertable/topical (patch) hormonal birth control products
are among the most effective forms of birth control. However, any form of birth control can fail. Therefore, I must use 2
different methods at the same time, every time I have sexual intercourse, even if 1 of the methods I choose is birth control
pills, injections, or tubal ligation (tube-tying).
Initial: ______
8. I understand that the following are considered effective forms of birth control:
Primary: Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
injectable/implantable/insertable/topical (patch) hormonal birth control products, and an IUD (intrauterine device).
Secondary: Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide, which is a special cream
or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial: ________
9. I will talk with my prescriber about any medicines or dietary supplements I plan to take during my Soriatane treatment
because hormonal birth control methods (for example, birth control pills) may not work if I am taking certain medicines or
herbal products (for example, St. John’s Wort).
Initial: ______
10. I understand that if I have taken Tegison (etretinate), I must continue to follow the birth control (contraception)
recommendations for Tegison.
Initial: ______
11. Unless I have had a hysterectomy or my prescriber says I have gone completely through menopause, I understand that I
must have 2 negative pregnancy test results before I can get a prescription for Soriatane. The first pregnancy test should be
done when my prescriber decides to prescribe Soriatane. The second pregnancy test should be done during the first 5 days
of my menstrual period right before starting Soriatane therapy, or as instructed by my prescriber. I will then have pregnancy
tests on a regular basis as instructed by my prescriber during my Soriatane therapy.
Initial: ______
12. I understand that I should not start taking Soriatane until I am sure that I am not pregnant and have negative results
from 2 pregnancy tests.
Initial: ______
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13. I have read and understand the materials my prescriber has given to me, including the Soriatane Pregnancy Prevention
Program. My prescriber gave me and asked me to watch the video about contraception (birth control). I was told about a
confidential counseling line that I may call at Roche for more information about birth control (1-800-542-6900).
14. I have received information on emergency contraception (birth control).
Initial: ______
15. I understand that I may receive a free contraceptive (birth control) counseling session and pregnancy testing. My
prescriber can give me a Soriatane Patient Referral Form for this free consultation.
Initial: ______
16. I understand that I should receive counseling from my prescriber, repeated on a regular basis, about contraception
(birth control) and behaviors associated with an increased risk of pregnancy.
Initial: ______
17. I understand that I must stop taking Soriatane right away and call my prescriber if I get pregnant, miss my menstrual
period, stop using birth control, or have sexual intercourse without using my 2 birth control methods during and at least 3
years after stopping Soriatane treatment.
Initial: ______
18. If I do become pregnant while on Soriatane or at any time within 3 years of stopping
Soriatane, I understand that I should report my pregnancy to Roche at 1-800-526-6367 or to
the Food and Drug Administration (FDA) MedWatch program at 1-800-FDA-1088. The
information I share will be kept confidential (private) and will help the company and the FDA
evaluate the pregnancy prevention program.
Initial: ______
My prescriber has answered all my questions about Soriatane. I understand that it is my responsibility not to get
pregnant during Soriatane treatment or for at least 3 years after I stop taking Soriatane. I now authorize my prescriber
________________ to begin my treatment with Soriatane.
Patient signature:________________________________ Date:____________________
Parent/guardian signature (if under age 18):____________________ Date:___________
Please print: Patient name and address________________________________________
______________________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and
the risks to females of childbearing potential. I have asked the patient if she has any questions regarding her treatment with
Soriatane and have answered those questions to the best of my ability.
Prescriber signature: ______________________________ Date:__________________
Medication Guide for Patients:
Read this Medication Guide carefully before you start taking Soriatane and read it each time
you get more Soriatane. There may be new information.
The first information in this Guide is about birth defects and how to avoid pregnancy. After this section there is
important safety information about possible effects for any patient taking Soriatane. ALL patients should read this
entire Medication Guide carefully.
This information does not take the place of talking with your prescriber about your medical
condition or treatment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 24
What is the most important information I should know about Soriatane?
Soriatane can cause severe birth defects. If you are a female who can get pregnant, you should use Soriatane only if you
are not pregnant now, can avoid becoming pregnant, and other medicines do not work for your severe psoriasis or you
cannot use other psoriasis medicines. Information about effects on unborn babies and about how to avoid pregnancy is
found in the next section: "What are the important warnings and instructions for females taking Soriatane?".
CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT
What are the important warnings and instructions for females taking Soriatane?
•
Before you receive your Soriatane prescription, you should have discussed and signed a Patient
Information/Consent form with your prescriber. This is to help make sure you understand the risk of birth
defects and how to avoid getting pregnant. If you did not talk to your prescriber about this and sign the Form,
contact your prescriber.
• You must not take Soriatane if you are pregnant or might become pregnant during
treatment or at any time for at least 3 years after you stop treatment because
Soriatane can cause severe birth defects.
•
During Soriatane treatment and for 2 months after you stop Soriatane treatment, you must avoid drinks, foods,
and all medicines that contain alcohol. This includes over-the-counter products that contain alcohol. Avoiding
alcohol is very important, because alcohol changes Soriatane into a drug that may take longer than 3 years to leave
your body. The chance of birth defects may last longer than 3 years if you swallow any form of alcohol during
Soriatane therapy and for 2 months after you stop taking Soriatane.
•
You and your prescriber must be sure you are not pregnant before you start Soriatane therapy. You must have
negative results from 2 pregnancy tests. A negative result shows you are not pregnant. Because it takes a few days
after pregnancy begins for a test to show that you are pregnant, the first negative test may not ensure you are not
pregnant. Do not take Soriatane until you have negative results from 2 pregnancy tests.
•
The first pregnancy test will be done at the time you and your prescriber decide if Soriatane might be right for
you.
•
The second pregnancy test will usually be done during the first 5 days of your menstrual period, right before you
plan to start Soriatane. Your prescriber may suggest another time.
• Discuss effective birth control (contraception) with your prescriber. You must use 2
effective forms of birth control (contraception) at the same time during all of the
following:
• for at least 1 month before beginning Soriatane treatment
• during treatment with Soriatane
• for at least 3 years after stopping Soriatane treatment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 25
• You must use 2 effective forms of birth control (contraception) at the same time
even if you think you cannot become pregnant, unless 1 of the following is true for
you:
• You had your womb (uterus) removed during an operation (a hysterectomy).
• Your prescriber said you have gone completely through menopause (the "change of
life").
• You choose a method called “abstinence”. This means that you are absolutely certain
(100% sure) you will not have sex with a male partner for at least 1 month before,
during, and for at least 3 years after Soriatane treatment.
• You can get a free birth control counseling session and pregnancy testing from a
prescriber or family planning expert. Your prescriber can give you a Soriatane
Patient Referral Form for this free session.
• You must use 2 effective forms of birth control (contraception) at the same time
every time you repeat Soriatane treatment. You must use birth control for at least 1
month before you start Soriatane, during treatment, and at least 3 years after you
stop Soriatane treatment.
• The following are considered effective forms of birth control:
Primary Forms:
• having your tubes tied (tubal ligation)
• partner’s vasectomy
• IUD (intrauterine device)
• birth control pills that contain both estrogen and progestin (combination oral
contraceptives)
• hormonal birth control products that are injected, implanted, or inserted in your body.
• birth control patch
Secondary Forms (use with a Primary Form):
• diaphragms with spermicide
• latex condoms with spermicide
• cervical caps with spermicide
At least 1 of your 2 methods of birth control must be a primary form.
•
If you have sex at any time without using 2 effective forms of birth control (contraception) at the same time, or if
you get pregnant or miss your period, stop using Soriatane and call your prescriber right away.
•
Consider “Emergency Contraception” (EC) if you have sex with a male without correctly using 2 effective forms
of birth control (contraception) at the same time. EC is also called “emergency birth control” or the “morning
after” pill. Contact your prescriber as soon as possible if you have sex without using 2 effective forms of birth control
(contraception) at the same time, because EC works best if it is used within 1 or 2 days after sex. EC is not a
replacement for your usual 2 effective forms of birth control (contraception) because it is not as effective as regular
birth control methods.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 26
You can get EC from private doctors or nurse practitioners, women’s health centers, or hospital emergency rooms. You
can get the name and phone number of EC providers nearest you by calling, the free Emergency Contraception Hotline
at 1-888-NOT-2-LATE (1-888-668-2528).
• Stop taking Soriatane right away and contact your prescriber if you get pregnant
while taking Soriatane or at any time for at least 3 years after treatment has
stopped. You need to discuss the possible effects on the unborn baby with your
prescriber.
•
If you do become pregnant while taking Soriatane or at any time for at least 3 years after stopping Soriatane,
you should report your pregnancy to Roche at 1-800-526-6367 or directly to the Food and Drug Administration
(FDA) MedWatch program (1-800-FDA-1088). Your name will be kept in private (confidential). The information
you share will help the FDA and the manufacturer evaluate pregnancy prevention program for Soriatane.
•
Do not take Soriatane if you are breast feeding. Soriatane can pass into your milk and may harm your baby. You
will need to choose either to breast feed or take Soriatane, but not both.
What should males know before taking Soriatane?
Small amounts of Soriatane are found in the semen of males taking Soriatane. Based upon available information, it appears
that these small amounts of Soriatane in semen pose little, if any, risk to an unborn child while a male patient is taking the
drug or after it is discontinued. Discuss any concerns you have about this with your prescriber.
All patients should read the rest of this Medication Guide
What is Soriatane?
Soriatane is a medicine used to treat severe forms of psoriasis in adults. Psoriasis is a skin
disease that causes cells in the outer layer of the skin to grow faster than normal and pile up
on the skin’s surface. In the most common type of psoriasis, the skin becomes inflamed and
produces red, thickened areas, often with silvery scales. Because Soriatane can have
serious side effects, you should talk with your prescriber about whether Soriatane’s
possible benefits outweigh its possible risks.
Soriatane may not work right away. You may have to wait 2 to 3 months before you get the
full benefit of Soriatane. Psoriasis gets worse for some patients when they first start
Soriatane treatment.
Soriatane has not been studied in children.
Who should not take Soriatane?
• Do NOT take Soriatane if you can get pregnant: Do not take Soriatane if you are
pregnant or might get pregnant during Soriatane treatment or at any time for at least 3
years after you stop Soriatane treatment. (see "What are the important warnings and
instructions for females taking Soriatane?").
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 27
• Do NOT take Soriatane if you are breast feeding. Soriatane can pass into your milk
and may harm your baby. You will need to choose either to breast feed or take Soriatane,
but not both.
• Do NOT take Soriatane if you have severe liver or kidney disease.
• Do NOT take Soriatane if you have repeated high blood lipids (fat in the blood).
• Do NOT take Soriatane if you take these medicines:
• methotrexate
• tetracyclines
The use of these medicines with Soriatane may cause serious side effects.
• Do NOT take Soriatane if you are allergic to acitretin, the active ingredient in
Soriatane, to any of the other ingredients (see the end of this Medication Guide for a list of
all the ingredients in Soriatane), or to any similar drugs (ask your prescriber or pharmacist
whether any drugs you are allergic to are related to Soriatane).
Tell your prescriber if you have or ever had:
• diabetes or high blood sugar
• liver problems
• kidney problems
• high cholesterol or high triglycerides (fat in the blood)
• heart disease
• depression
• alcoholism
• an allergic reaction to a medication
Your prescriber needs this information to decide if Soriatane is right for you and to know what
dose is best for you.
Tell your prescriber about all the medicines you take, including prescription and non-
prescription medicines, vitamins, and herbal supplements. Some medicines can cause
serious side effects if taken while you also take Soriatane. Some medicines may affect how
Soriatane works, or Soriatane may affect how your other medicines work. Be especially
sure to tell your prescriber if you are taking the following medicines:
• methotrexate
• tetracyclines
• phenytoin
• vitamin A supplements
• progestin-only oral contraceptives ("mini-pills")
• Tegison® or Tigason (etretinate). Tell your prescriber if you have ever taken this medicine
in the past.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 28
• St. John's Wort herbal supplement
Tell your prescriber if you are getting phototherapy treatment. Your doses of
phototherapy may need to be changed to prevent a burn.
How should I take Soriatane?
•
Take Soriatane with food.
•
Be sure to take your medicine as prescribed by your prescriber. The dose of Soriatane varies from patient to patient.
The number of capsules you must take is chosen specially for you by your prescriber. This dose may change during
treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose and resume your
normal schedule.
• If you take too much Soriatane (overdose), call your local poison control center or
emergency room.
You should have blood tests for liver function, cholesterol and triglycerides before starting
treatment and during treatment to check your body's response to Soriatane. Your prescriber
may also do other tests.
Once you stop taking Soriatane, your psoriasis may return. Do not treat this new psoriasis
with leftover Soriatane. It is important to see your prescriber again for treatment
recommendations because your situation may have changed.
What should I avoid while taking Soriatane?
•
Avoid pregnancy. See "What is the most important information I should know about Soriatane?", and “What are the
important warnings and instructions for females taking Soriatane?”.
•
Avoid breast feeding. See “What are the important warnings and instructions for females taking Soriatane?”
• Avoid alcohol. Females must avoid drinks, foods, medicines, and over-the-counter
products that contain alcohol The risk of birth defects may continue for longer than 3
years if you swallow any form of alcohol during Soriatane treatment and for 2 months after
stopping Soriatane (see "What are the important warnings and instructions for females
taking Soriatane?").
•
Avoid giving blood. Do not donate blood while you are taking Soriatane and for at least 3 years after stopping
Soriatane treatment. Soriatane in your blood can harm an unborn baby if your blood is given to a pregnant woman.
Soriatane does not affect your ability to receive a blood transfusion.
•
Avoid progestin-only birth control pills (“mini-pills”). This type of birth control pill may not work while you take
Soriatane. Ask your prescriber if you are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop taking
Soriatane and call your prescriber if this occurs (see Side Effects).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 29
•
Avoid non-medical ultraviolet (UV) light. Soriatane can make your skin more sensitive to UV light. Do not use
sunlamps, and avoid sunlight as much as possible. If you are taking light treatment (phototherapy), your prescriber
may need to change your light dosages to avoid burns.
•
Avoid dietary supplements containing Vitamin A. Soriatane is related to vitamin A. Therefore, do not take
supplements containing vitamin A, because they may add to the unwanted effects of Soriatane. Check with your
prescriber or pharmacist if you have any questions about vitamin supplements.
•
DO NOT SHARE Soriatane with anyone else, even if they have the same symptoms. Your medicine may harm
them or their unborn child.
What are the possible side effects of Soriatane?
• Soriatane can cause birth defects. See "What is the most important information I should
know about Soriatane?" and "What are the important warnings and instructions for
females taking Soriatane?"
• Psoriasis gets worse for some patients when they first start Soriatane treatment. Some
patients have more redness or itching. If this happens, tell your prescriber. These
symptoms usually get better as treatment continues, but your prescriber may need to
change the amount of your medicine.
• Serious side effects. These do not happen often, but they can lead to permanent harm,
or rarely, to death. Stop taking Soriatane and call your prescriber right away if you get the
following signs or symptoms:
•
Bad headaches, nausea, vomiting, blurred vision. These symptoms can be signs of increased brain pressure that
can lead to blindness or even death.
•
Decreased vision in the dark (night blindness). Since this can start suddenly, you should be very careful when
driving at night. This problem usually goes away when Soriatane treatment stops. If you develop any vision
problems or eye pain stop taking Soriatane and call your prescriber.
•
Depression. There have been some reports of patients developing mental problems including a depressed mood,
aggressive feelings, or thoughts of ending their own life (suicide). These events, including suicidal behavior, have
been reported in patients taking other drugs similar to Soriatane as well as in patients taking Soriatane. Since other
things may have contributed to these problems, it is not known if they are related to Soriatane. It is very important
to stop taking Soriatane and call your prescriber right away if you develop such problems.
•
Yellowing of your skin or the whites of your eyes, nausea and vomiting, loss of appetite, or dark urine.
These can be signs of serious liver damage.
•
Aches or pains in your bones, joints, muscles, or back; trouble moving; loss of feeling in your hands or feet.
These can be signs of abnormal changes to your bones or muscles.
• Frequent urination, great thirst or hunger. Soriatane can affect blood sugar control, even if you do not already
have diabetes. These are some of the signs of high blood sugar.
•
Shortness of breath, dizziness, nausea, chest pain, weakness, trouble speaking, or swelling of a leg. These
may be signs of a heart attack, blood clots, or stroke. Soriatane can cause serious changes in blood fats (lipids).
It is possible for these changes to cause blood vessel blockages that lead to heart attacks, strokes, or blood clots.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 30
Common side effects. If you develop any of these side effects or any unusual reaction, check with your prescriber to find
out if you need to change the amount of Soriatane you take. These side effects usually get better if the Soriatane dose is
reduced or Soriatane is stopped.
•
Chapped lips; peeling fingertips, palms, and soles; itching; scaly skin all over; weak nails; sticky or fragile
(weak) skin; runny or dry nose, or nose bleeds. Your prescriber or pharmacist can recommend a lotion or cream to
help treat drying or chapping.
•
Dry mouth
•
Joint pain
•
Tight muscles
•
Hair loss. Most patients have some hair loss, but this condition varies among patients. No one can tell if you will lose
hair, how much hair you may lose or if and when it may grow back.
•
Dry, eyes. Soriatane may dry your eyes. Wearing contact lenses may be uncomfortable during and after treatment
with Soriatane because of the dry feeling in your eyes. If this happens, remove your contact lenses and call your
prescriber. Also read the section about vision under “Serious side effects”.
•
Rise in blood fats (lipids). Soriatane can cause your blood fats (lipids) to rise. Most of the time this is not serious. But
sometimes the increase can become a serious problem. (See information under “Serious side effects.”). You should
have blood tests as directed by your prescriber.
These are not all the possible side effects of Soriatane. For more information, ask your
prescriber or pharmacist.
How should I store Soriatane?
Keep Soriatane away from sunlight, high temperature, and humidity. Keep Soriatane away
from children.
What are the ingredients in Soriatane?
Active ingredient: acitretin
Inactive
ingredients:
microcrystalline
cellulose,
sodium
ascorbate,
gelatin,
black
monogramming ink and maltodextrin (a mixture of polysaccharides). Gelatin capsule shells
contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide. They may also
contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium disodium.
General information about the safe and effective use of Soriatane
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Soriatane for a condition for which it was not prescribed. Do not give
Soriatane to other people, even if they have the same symptoms that you have.
This Medication Guide summarizes the most important information about Soriatane. If you would like more information,
talk with your prescriber. You can ask your pharmacist or prescriber for information about Soriatane that is written for
health professionals.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 31
Tegison® is a registered trademark of Hoffmann-La Roche Inc.
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 32
27898424
Revised: March 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 33
Copyright ©1997-2003 by Roche Laboratories Inc. All rights reserved.
End of Professional Labeling
Pregnancy Prevention Program (PPP) Booklet
(the section below in yellow highlight is not part of labeling; intended as sponsor communication in Approval)
• The Pregnancy Prevention Program booklet forms are not available in Word format and
so the following Comments were sent to sponsor and were agreeable.
•
This first comment regards the Introduction for the self-assessment test. This is a suggestion; it can stand as is
at your discretion. Use of the word “test” may discourage some patients from cooperating with this voluntary
program. Perhaps you could re-phrase the instructions to say: “Answer the patient self-evaluation questions”.
On the “test” form itself, it might also intimidate some patients that they are asked to sign and date the
completed “test” for the medical record with wrong answers noted. Is this really necessary given that they will
already be signing a Consent Form? Also, consider instructing the patient to mark “unsures” and wrong
answers with a “X” instead of a checkmark. The reason is that a busy prescriber is apt to misinterpret the
checkmark as “OK”, whereas a “X” is likely more universally recognized as a problem that needs further
counseling.
•
Page 26 of the self-assessment tool states that “Soriatane is a very powerful medicine used to treat severe
psoriasis that did not get better with other treatments”. This should be deleted. Instead, insert:: “Soriatane can
have serious side effects. For that reason, it is used to treat only severe psoriasis. It should NEVER be taken
by a pregnant woman”.
•
It appears that there is plenty of space in the mock up section for females, so please increase the “white space”
between bullets for readability.
•
The automated phone line has a title “what should I do if I think I am pregnant”, but this important
information should be included as well immediately before the emergency contraception section: insert “What
should I do if I think I am pregnant or if I have trouble with my birth control” (answer: STOP taking Soriatane
and call prescriber immediately if you suspect you might be pregnant; if problems with birth control, STOP
Soriatane, call prescriber immediately, and re-read the next section on emergency contraception”).
•
On page 13 of the booklet please delete the words “The facts in this booklet about Soriatane treatment are
very important to your health and well-being”. Insert instead these words: “It is very important that you
understand all of the facts in this booklet because Soriatane can have serious side effects”.
The booklet recommended for approval is as submitted by the sponsor below with the changes noted above, including
wording changes to match the Medication Guide and Informed Consent (end of comment):
Soriatane® (acitretin) Pregnancy Prevention Program
((PPP Logo))
Pages
CONTENTS
Your Personal Record............................................................................................................................. 1
Patient Product Information: Important information.......................................................…… 2-11
concerning your treatment with Soriatane (acitretin)
Preventing Pregnancy: A Guide to Contraception............................................................. 12-28
Contraception Counseling Referral Program and Form........................ Inside Back Pocket
Patient Self-evaluation ....................................................................................... Inside Back Pocket
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 34
Soriatane Patient Agreement/Informed Consent
for Female Patients........................................................................................... Inside Back Pocket
INTRODUCTION
Please read this booklet carefully before taking Soriatane (soh-RYE-uh-tane). This booklet provides important
facts about Soriatane, but it does not contain all the information about this medication. When you pick up your
Soriatane prescription at the pharmacy, you will receive a copy of the Soriatane Medication Guide. If there’s
anything else you want to know, or if you have any questions or concerns, talk with your prescriber.
Please follow these simple steps to using this booklet:
1. Read the Patient Product Information
• Read this section carefully for important information about this medication. The information
presented here is taken from the Soriatane Medication Guide.
2. Next, read the section Preventing Pregnancy: A Guide to Contraception
• Read this section for important information about primary and secondary contraception
methods, free contraception counseling, and how to use the Confidential Contraception
Counseling Line.
• Talk to your prescriber about getting a referral for contraception counseling. If counseling is desired, your
prescriber should complete the Soriatane Patient Referral Form (located in the back pocket of this booklet); you
will need to bring this form to your appointment for contraception counseling.
3. Take the patient self-evaluation test
• Test yourself using the self-evaluation form (enclosed in the back pocket of this booklet) to make sure you
fully understand the information and to help you and your prescriber decide whether you are ready to start
taking Soriatane.
4. Sign the Patient Agreement/Informed Consent for Female Patients form if you and your prescriber have
decided that Soriatane treatment is right for you.
• Discuss and complete the Patient Agreement/Informed Consent for Female Patients form with your
prescriber.
Copyright © 2003 by Roche Laboratories Inc. All rights reserved.
YOUR PERSONAL RECORD
Name: __________________________________________________________________________
You MUST have negative results from 2 pregnancy tests done by your prescriber that show you are NOT
pregnant before starting Soriatane therapy.
First test will be done at the time you and your prescriber decide if Soriatane might be right for you.
TEST DATE: ______________________________TEST RESULT:_____________________________
Second test will usually be done during the first 5 days of your menstrual period, right before you plan to start
Soriatane, but your prescriber may suggest another time.
START OF MENSTRUAL PERIOD: ___________________
TEST DATE: ______________________________TEST RESULT: _____________________________
DATE SORIATANE THERAPY STARTED: ______________
FOLLOW-UP APPOINTMENTS
DATE ___________________________________TIME ____________________________________
DATE ___________________________________TIME ____________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 35
DATE ___________________________________TIME ____________________________________
DATE ___________________________________TIME ____________________________________
DATE ___________________________________TIME ____________________________________
DATE ___________________________________TIME ____________________________________
WHAT IS THE MOST IMPORTANT
INFORMATION I SHOULD KNOW
ABOUT SORIATANE?
Soriatane can cause severe birth defects. If you are a female who can get pregnant, you should use Soriatane
only if you are not pregnant now, can avoid becoming pregnant, and other medicines do not work for your
severe psoriasis or you cannot use other psoriasis medicines. Females should read “What are the important
warnings and instructions for females taking Soriatane?” on page 3 and “What should males know before
taking Soriatane?” on page 6. Everyone should read this entire booklet carefully.
IMPORTANT INFORMATION
FOR FEMALE PATIENTS
What are the important warnings and instructions for females taking Soriatane?
• Before you received your Soriatane prescription, you should have discussed and signed a Patient
Agreement/Informed Consent for Female Patients form with your prescriber. This is to help make sure you
understand the risk of birth defects and how to avoid getting pregnant. If you did not talk to your prescriber
about this and sign the form, contact your prescriber.
• You must not take Soriatane if you are pregnant or might become pregnant during treatment or at any time
for at least 3 years after you stop treatment because Soriatane can cause severe birth defects.
• During Soriatane treatment and for 2 months after you stop Soriatane treatment, you must avoid drinks,
food and all medicines that contain alcohol. This includes over-the-counter
products that contain alcohol. Avoiding alcohol is very important, because alcohol changes Soriatane into a
drug that may take longer than 3 years to leave your body. The chance of birth defects may last longer than 3
years if you swallow any form of alcohol during Soriatane therapy and for 2 months after you stop taking
Soriatane.
• You and your prescriber must be sure you are not pregnant before you start Soriatane therapy. You must
have negative results from 2 pregnancy tests. A negative result shows you are not pregnant. Because it takes a
few days after pregnancy begins for a test to show that you are pregnant, the first negative test may not ensure
you are not pregnant. Do not take Soriatane until you have negative results from 2 pregnancy tests.
- The first pregnancy test will be done at the time you and your prescriber decide if
Soriatane might be right for you.
- The second pregnancy test will usually be done during the first 5 days of your
menstrual period, right before you plan to start Soriatane. Your prescriber may
suggest another time.
• Discuss effective birth control (contraception) with your prescriber. You must use 2 effective forms of birth
control (contraception) at the same time during all of the following:
- For at least 1 month before beginning Soriatane treatment
– During treatment with Soriatane
– For at least 3 years after stopping Soriatane treatment
• You must use 2 effective forms of birth control (contraception) at the same time even if you think you cannot
become pregnant, unless 1 of the following is true for you:
- You have had your womb (uterus) removed during an operation (a hysterectomy).
- Your prescriber said you have gone completely through menopause (the “change of life”).
- You choose a method called “abstinence.” This means that you are absolutely certain
(100% sure) you will not have sex with a male partner for at least 1 month before, during
and for at least 3 years after Soriatane treatment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 36
• You can get a free birth control counseling session and pregnancy testing from a prescriber or family planning
expert. Your prescriber can give you a Soriatane Patient Referral Form for this free session.
• The following are considered effective forms of birth control:
Primary Forms
- having your tubes tied (tubal ligation)
- partner’s vasectomy
- IUD (intrauterine device)
- birth control pills that contain both estrogen and progestin
(combination oral contraceptives)
- hormonal birth control products that are injected, implanted or inserted in your body
- birth control patch
Secondary Forms (use with a Primary Form)
- diaphragms with spermicide
- latex condoms with spermicide
- cervical caps with spermicide
At least 1 of your 2 methods of birth control must be a primary form.
• You must use 2 effective forms of birth control (contraception) at the same time every time you repeat
Soriatane treatment. You must use birth control for at least 1 month before you start Soriatane, during treatment
and for at least 3 years after you stop Soriatane treatment.
• If you have sex at any time without using 2 effective forms of birth control (contraception) at the same
time, or if you get pregnant or miss your period, stop using Soriatane and call your prescriber right away.
• Consider “Emergency Contraception (EC)” if you have sex with a male without correctly using 2 effective
forms of birth control (contraception) at the same time. EC is also called “emergency birth control” or the
“morning after” pill. Contact your prescriber as soon as possible if you have sex without using 2 effective forms
of birth control (contraception) at the same time, because EC works best if it is used within 1 or 2 days after sex.
EC is not a replacement for your usual 2 effective forms of birth control (contraception) because it is not as
effective as regular birth control methods.
You can get EC from: private doctors or nurse practitioners, women’s health centers or hospital emergency
rooms. You can get the name and phone number of EC providers nearest you by calling the free Emergency
Contraception Hotline at 1-888-NOT-2-LATE (1-888-668-2528).
• Stop taking Soriatane right away and contact your prescriber if you get pregnant while taking Soriatane or
at any time for at least 3 years after treatment has stopped. You need to discuss the possible effects on the
unborn baby with your prescriber.
• If you do become pregnant while taking Soriatane or at any time for at least 3 years after stopping
Soriatane, you should report your pregnancy to Roche at 1-800-526-6367 or directly to the Food and Drug
Administration (FDA) MedWatch program (1-800-FDA-1088).
Your name will be kept in private (confidential). The information you share may help the FDA and the
manufacturer support the pregnancy prevention program for Soriatane.
• Do not take Soriatane if you are breast-feeding. Soriatane can pass into your milk and may harm your baby.
You will need to choose either to breast-feed or take Soriatane but not both.
IMPORTANT INFORMATION
FOR MALE PATIENTS
What should males know before taking Soriatane?
Small amounts of Soriatane are found in the semen of males taking Soriatane. Based upon available information
both during and after the treatment, small amounts of Soriatane in semen do not seem to harm the baby. It is
not known for sure that there is a risk. It appears that any small remaining amount of Soriatane in semen poses
little, if any, risk to an unborn child while a male patient is taking the drug or after it is discontinued. Discuss
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any concerns you have about this with your prescriber.
.
IMPORTANT INFORMATION
FOR ALL PATIENTS
What is Soriatane (acitretin)?
Soriatane is a medicine used to treat severe forms of psoriasis in adults. Psoriasis is a skin disease that causes
cells in the outer layer of the skin to grow faster than normal and pile up on the skin’s surface. In the most
common type of psoriasis, the skin becomes inflamed and produces red, thickened areas, often with silvery
scales. Because Soriatane can have serious side effects, you should talk with your prescriber about whether
Soriatane’s possible benefits outweigh its possible risks.
Soriatane may not work right away. You may have to wait 2 to 3 months before you get the full benefit of
Soriatane. Psoriasis gets worse for some patients when they first start Soriatane treatment.
Soriatane has not been studied in children.
Who should not take Soriatane?
• Do NOT take Soriatane if you can get pregnant: Do not take Soriatane if you are pregnant or might get
pregnant during Soriatane treatment or at any time for at least 3 years after you stop Soriatane treatment (see
"What are the important warnings and instructions for females taking Soriatane?" on page 3).
• Do NOT take Soriatane if you are breast-feeding. Soriatane can pass into your milk and may harm your
baby. You will need to choose either to breast-feed or take Soriatane, but not both.
• Do NOT take Soriatane if you have severe liver or kidney disease.
• Do NOT take Soriatane if you have repeated high blood lipids over time (fat in the blood).
• Do NOT take Soriatane if you take the medicines:
– methotrexate
– tetracyclines
The use of these medicines with Soriatane may cause serious side effects.
• Do NOT take Soriatane if you are allergic to acitretin, the active ingredient in Soriatane, or to any of the
other ingredients. (See the end of this section for a list of all the ingredients in Soriatane).
Tell your prescriber if you have or ever had:
• Diabetes or high blood sugar
• Liver problems
• Kidney problems
• High cholesterol or high triglycerides (fat in the blood)
• Heart disease
• Depression
• Alcoholism
Your prescriber needs this information to decide if Soriatane is right for you and to know what dose is best for
you.
Tell your prescriber about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines can cause serious side effects if taken while you also take
Soriatane. Some medicines may affect how Soriatane works, or Soriatane may affect how your other medicines
work. Be especially sure to tell your prescriber if you are taking the following medicines:
• methotrexate
• tetracyclines
• phenytoin
• vitamin A supplements
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• progestin-only oral contraceptives ("mini-pills")
• Tegison® or Tigason® (etretinate). Tell your prescriber if you have ever taken this medicine in the past.
• St. John's Wort herbal supplement
Tell your prescriber if you are getting phototherapy treatment. Your doses of phototherapy may need to be
changed to prevent a burn.
How should I take Soriatane?
• Take Soriatane with food.
• Be sure to take your medicine as prescribed by your prescriber. The dose of Soriatane varies from patient to
patient. The number of capsules you must take is chosen specially for you by your prescriber. This dose may
change during treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose, and resume your
normal schedule.
• If you take too much Soriatane (overdose), call your local poison control center or emergency room.
You should have blood tests for liver function, cholesterol and triglycerides before starting treatment and
during treatment to check your body's response to Soriatane. Your prescriber may also do other tests.
Tegison® is a registered trademark of Hoffmann-La Roche Inc. Tigason® is a registered trademark of F.
Hoffmann-La Roche AG.
Once you stop taking Soriatane, your psoriasis may return. Do not treat this new psoriasis with leftover
Soriatane. It is important to see your prescriber again for treatment recommendations because your situation
may have changed.
What should I avoid while taking Soriatane?
• Avoid pregnancy. See "What is the most important information I should know about Soriatane?" on page 2,
"What are the important warnings and instructions for females taking Soriatane?" on page 3, and "What should
males know before taking Soriatane?" on page 6.
• Avoid breast-feeding. See "What are the important warnings and instructions for females taking Soriatane?"
• Avoid alcohol. Females must avoid drinks, foods, medicines and over-the-counter products that contain
alcohol. The risk of birth defects may continue for longer than 3 years if you swallow any form of alcohol during
Soriatane treatment or for 2 months after stopping Soriatane (see “What are the important warnings and
instructions for females taking Soriatane?” on page 3).
• Avoid giving blood. Do not donate blood while you are taking Soriatane and for at least 3 years after
stopping Soriatane treatment. Soriatane in your blood can harm an unborn baby if your blood is given to a
pregnant woman. Soriatane does not affect your ability to receive a blood transfusion.
• Avoid progestin-only birth control pills ("mini-pills"). They may not work while you take Soriatane. Ask
your prescriber if you are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop taking Soriatane and call your
prescriber if this occurs (see the Serious side effects section on the next page).
• Avoid nonmedical ultraviolet (UV) light. Soriatane can make your skin more sensitive to UV light. Do not
use sunlamps, and avoid sunlight as much as possible. If you are taking light treatment (phototherapy), your
prescriber may need to change your light dosages to avoid burns.
• Avoid dietary supplements containing Vitamin A. Soriatane is related to vitamin A. Therefore, do not take
supplements containing vitamin A, because they may add to the unwanted effects of Soriatane. Check with
your prescriber or pharmacist if you have any questions about vitamin supplements.
• DO NOT SHARE Soriatane with anyone else, even if they have the same symptoms.
What are the possible side effects of Soriatane?
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Soriatane can cause birth defects. See "What is the most important information I should know about
Soriatane?" on page 2 and "What are the important warnings and instructions for females taking Soriatane?" on
page 3.
Psoriasis gets worse for some patients when they first start Soriatane treatment. Some patients have more
redness or itching. If this happens, tell your prescriber. These symptoms usually get better as treatment
continues, but your prescriber may need to change the amount of your medicine.
Serious side effects
These do not happen often, but they can lead to permanent harm, or rarely, to death. Stop taking Soriatane and
call your prescriber right away if you get the following signs or symptoms:
• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be signs of increased brain pressure
that can lead to blindness or even death.
• Decreased vision in the dark (night blindness). Since this can start suddenly, you should be very careful
when driving at night. This problem usually goes away when Soriatane treatment stops. If you develop any
vision problems or eye pain, stop taking Soriatane and call your prescriber.
• Depression. There have been some reports of patients who have taken oral retinoids like Soriatane and have
developed mental problems including a depressed mood, aggressive feelings or thoughts of self-harm. Since
other factors may have contributed to such events, it is not known if they are related to Soriatane. It is very
important to stop taking Soriatane and call your prescriber right away if you experience any of these.
• Yellowing of your skin or the whites of your eyes, nausea and vomiting, loss of appetite or dark urine.
These can be signs of serious liver damage.
• Aches or pains in your bones, joints, muscles or back; trouble moving; loss of feeling in your hands or feet.
These can be signs of abnormal changes to your bones or muscles.
• Frequent urination, great thirst or hunger. Soriatane can affect blood sugar control, even if you do not
already have diabetes. These are some of the signs of high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble speaking or swelling of a leg. These
may be signs of a heart attack, blood clots or stroke. Soriatane can cause serious changes in blood fats (lipids).
It is possible for these changes to cause blood vessel blockages that lead to heart attacks, strokes or blood clots.
Common side effects
If you develop any of these side effects or any unusual reaction, check with your prescriber to find out if you
need to change the amount of Soriatane you take. These side effects usually get better if you reduce your dose or
stop taking Soriatane:
• Chapped lips; peeling fingertips, palms and soles; itching; scaly skin all over; weak nails;
sticky or fragile (weak) skin; runny or dry nose or nose bleeds. Your prescriber or pharmacist can recommend
a lotion or cream to help treat drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
• Hair loss. Most patients have some hair loss, but this condition varies among patients. No one
can tell if you will lose hair, how much hair you may lose or if and when it may grow back.
• Dry eyes. Soriatane may dry your eyes. Wearing contact lenses may be uncomfortable during and after
treatment with Soriatane because of the dry feeling in your eyes. If this happens, remove your contact lenses
and call your prescriber. Also read about decreased vision in the Serious side effects section on the previous
page.
• Rise in blood fats (lipids). Soriatane can cause your blood fats (lipids) to rise. Most of the time, this is not
serious. But sometimes, the increase can become a serious problem. (See information in the Serious side effects
section on the previous page.) You should have blood tests as directed by your prescriber.
These are not all the possible side effects of Soriatane. For more information, ask your prescriber or pharmacist.
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How should I store Soriatane?
Keep Soriatane away from sunlight, high temperature and humidity. Keep Soriatane away from children.
What are the ingredients in Soriatane?
Active ingredient: acitretin
Inactive ingredients: microcrystalline cellulose, sodium ascorbate, gelatin, black monogramming ink and
maltodextrin (a mixture of polysaccharides). Gelatin capsule shells contain gelatin, iron oxide (yellow, black and
red) and titanium dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate
calcium disodium.
General information about the safe and effective use of Soriatane
Medicines are sometimes prescribed for purposes other than those listed here. Do not use Soriatane for a
condition for which it was not prescribed. Do not give Soriatane to other people, even if they have the same
symptoms that you have.
This section of this booklet summarizes the most important information about Soriatane. If you would like more
information, talk with your prescriber. You can ask your pharmacist or prescriber for information about
Soriatane that is written for health professionals.
PREVENTING PREGNANCY:
A GUIDE TO CONTRACEPTION
Why is this information very important to me?
Your dermatologist may prescribe Soriatane (acitretin) to be used in your treatment. Soriatane is used to treat
severe psoriasis in adults. In females of reproductive potential, Soriatane should be reserved for nonpregnant
patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other
treatments. Soriatane can cause severe birth defects. Soriatane is indicated only for females who are not
pregnant. This booklet contains very important facts about Soriatane that you must know and understand
before you can begin treatment with Soriatane.
This section of the booklet explains the birth control (contraception) steps you must take before
you can start taking Soriatane; what you must do during Soriatane treatment; and what you must do for at least
3 years after you stop your Soriatane treatment.
To help you avoid becoming pregnant while taking Soriatane, a special Contraception Counseling Referral
Program is available through your prescriber that will pay for you to go to another healthcare professional to
receive contraception counseling and pregnancy testing. Details of this program are given in the section called
Contraception Counseling Referral Program, on page 14.
Emergency Contraception (EC), or emergency birth control, is used to prevent pregnancy following unprotected
intercourse or sex. Details on emergency birth control are provided in the section called Emergency Contraception,
on page 24.
Also, it is extremely important that your sexual partner understand that you must use 2 effective forms of birth
control (contraception) at the same time for at least 1 month before beginning Soriatane treatment, during
treatment with Soriatane and for at least 3 years after stopping Soriatane treatment. It is very important that
your sexual partner understand you must not become pregnant and the special precautions that must be taken
during Soriatane treatment and for at least 3 years after you completely stop taking Soriatane. The section called
Your sexual partner, on page 26, is provided to help you as you talk to your sexual partner about his important
role in your Soriatane treatment.
Because you need to understand all the facts in this booklet, read it all the way through. Do NOT skip any
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section of the booklet. After you have read through the booklet once, read it through again. As you read
through the second time, write down a list of questions for your prescriber to answer. Do not worry if you think
the question is silly or may be unimportant. You have to understand all the facts in this booklet. Your prescriber
wants you to understand everything in this booklet and everything that he or she tells you about Soriatane
treatment. The facts in this booklet about Soriatane treatment are very important to your health and well-being.
Why must I use 2 effective forms of birth control (contraception)?
You must use 2 effective forms of birth control (contraception) at the same time for at least 1 month before
beginning Soriatane treatment, during treatment with Soriatane and for at least 3 years after stopping
Soriatane treatment to prevent pregnancy, because any birth control method can fail and your baby could be
born with severe birth defects if you are taking Soriatane while you are pregnant.
There is an extremely high risk that a deformed baby can result if you become pregnant while taking Soriatane
in any amount, even for short periods of time. When an unborn baby is exposed to Soriatane, there is a higher
risk of deformities or a miscarriage. This explains the need for the precautions that must be taken at least 1
month before, during and for at least 3 years after stopping Soriatane use. Remember, not 1 but 2 effective
forms of birth control are required while you are taking Soriatane.
CONTRACEPTION COUNSELING
REFERRAL PROGRAM
Be sure to ask your prescriber about the Contraception Counseling
Referral Program
Before you can start taking Soriatane (acitretin), you and your prescriber must be sure that
you are not pregnant and that you understand how to avoid becoming pregnant. Because it is
so very important that you understand how to avoid becoming pregnant while taking
Soriatane, a special Contraception Counseling Referral Program has been established by the
manufacturer of Soriatane.
You or your prescriber can arrange for you to see a contraception counselor who specializes in the female
reproductive system. This healthcare professional will provide you with expert counseling about birth control
and may even do a pregnancy test.
Even if you feel that you know about birth control, and even if you are not having sex or do not plan to have
sex, this counseling is very important in planning your treatment with Soriatane. You will not be required to
pay for the counseling or any pregnancy testing that they may do. Be sure to ask your prescriber about the
Contraception Counseling Referral Program.
What is abstinence?
Abstinence means that you are absolutely certain (100% sure) you will not have sex with a male partner for at
least 1 month before, during, and for at least 3 years after Soriatane treatment.
Abstinence is not considered a method of birth control.
Using abstinence
If you are not currently having sexual intercourse with a male partner, it is extremely important that you ask
yourself:
Will I definitely remain abstinent for at least 1 month before, during and for at least 3 years after
Soriatane treatment?
If your answer is no, talk to your prescriber immediately.
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How can I avoid becoming pregnant?
Any method of birth control can fail. Even if you use one of the most effective birth control methods correctly,
there is still a risk of getting pregnant.
Therefore, 2 effective forms of birth control must always be used together at the same time by female
patients starting at least 1 month before, during and at least 3 years after Soriatane treatment.
CONTRACEPTION METHODS1
Primary (most effective) methods of birth control
At least 1 of the 2 effective forms of birth control must be a primary method of birth control.
This information does not contain all available information about contraception. As always, you should discuss
this and any other medical question with your prescriber or contraception counselor.
THE PILL (oral contraception)
Two kinds of birth control pills are available and they work in different ways.
Combination pills, which contain 2 hormones, thicken vaginal mucus to keep the sperm from joining the egg,
and may prevent a fertilized egg from attaching to the womb. In addition, combination pills prevent eggs from
being released. Your healthcare professional will discuss the different types of pills and help you decide which
one is right for you.
Mini-pills, which contain only 1 type of hormone, thicken vaginal mucus to keep the sperm from joining the
egg, and may prevent a fertilized egg from attaching to the womb. Mini-pills are not recommended for birth
control during Soriatane (acitretin) use.
With the Pill method of birth control, 1 pill is taken once a day until the package is completed.
The Pill is usually started the first Sunday after a normal menstrual period or as instructed by your healthcare
professional. One package is completed every menstrual cycle. Not all pills provide protection from the start;
you can become pregnant during the first 4 weeks after you start taking the Pill. Pills should be taken at the
same time every day, and it may be helpful to use a calendar. Strike an “X” for the first day of a new package of
pills, and check each day thereafter.
With perfect use (correctly and consistently), about 1 woman in 1000 becomes pregnant.
For typical use (not always correctly or consistently), the rate is 5 in 100.
The Pill can have a variety of side effects; most are considered minor. Some rare, but serious, health risks do
exist, including blood clots, heart attack and stroke. Women who are older than 35 years, who smoke or who are
greatly overweight are at greater risk for these side effects, so it is important to discuss these issues with your
prescriber.
If a dose of the combination pill is missed, you can take one when you realize it and then continue taking the
others at their regular time. If you miss an entire day, it may be okay to take 2 pills together if necessary;
however, you should consult the patient information included in your birth control package and contact
your healthcare professional. If you miss taking your pills more than 2 days in a row, you can become
pregnant. Do not have sexual intercourse at this time. If you miss more than 2 days, you should call your
healthcare professional as soon as you realize it. You are at greatest risk for pregnancy if you start a package
late or miss taking pills during the first week of each package.
Remember: If the Pill is your primary method, you must still use a secondary method at the same time.
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THE PATCH (topical contraceptive)
The 2 hormones in the contraceptive patch are absorbed through the skin and released into the bloodstream
while the patch is worn. The hormones in the contraceptive patch thicken vaginal mucus to keep the sperm
from joining the egg and may prevent a fertilized egg from attaching to the womb. They also prevent eggs from
being released.
With the 4-week patch method of birth control, 1 patch is used per week for 3 weeks; then, no patch is worn for
the fourth week. The first patch may be applied on the first day of a woman’s menstrual period (First Day Start)
OR on the first Sunday after the woman’s menstrual period starts (Sunday Start). If Sunday Start is selected, or
the patch is applied on any other day except the first day of the menstrual period, a woman may become
pregnant during the first week of her cycle. The patch should be changed on the same day each week.
The effectiveness of the patch is considered to be similar to combination contraceptive pills if used as directed.
However, the patch may be less effective for a woman who weighs more than 198 lb (90 kg). Your healthcare
professional should discuss your individual needs with you if your weight is more than 198 lb.
The patch may have similar side effects to combination contraceptive pills. Most side effects are considered
minor. However, some rare but serious side effects include blood clots, heart attack and stroke. Women who are
older than 35 years, who smoke or who are significantly overweight are at greater risk for these side effects.
If the patch falls off or is partially detached for less than 24 hours, a new patch should be put on
immediately, and this patch should be changed on the usual change day. If the patch is detached for more
than 1 day, a new cycle with a new change day should be started by applying a new patch. Should this occur,
you may not be protected from pregnancy for the first week. Do not have sexual intercourse at this time.
If you forget to apply a patch on the first day of your cycle or forget to change a patch for more than 2 days in
the middle of the cycle, you should apply a new patch immediately and begin a new 4-week cycle with a
new change day. You may not be protected from pregnancy for the next week. It is very important that no
more than 7 days elapse during the patch-free week of treatment. Do not have sexual intercourse at this time.
Consult your healthcare professional if you forget to follow the instructions in the patient information
included with your patch.
Remember: If the patch is your primary method, you must still use a secondary method at the same time.
IMPLANTABLE HORMONES—This method of birth control is no longer available to new patients.
With this birth control method, your healthcare professional puts 6 small rod-shaped capsules under the skin of
your upper arm. The procedure is simple and can be done during an office visit. The capsules release small
amounts of hormone that stop eggs from being released and thicken vaginal mucus to keep sperm from joining
the egg. The capsules remain effective for a number of years, and they can be removed by your healthcare
professional at any time.
Generally, the side effects are similar to those that occur if you take the Pill. There is only a small chance of an
irritation at the spot where the capsules are implanted. The contraceptive effectiveness of these hormones
begins 3 days after being implanted.
With perfect use, about 5 women in 10,000 become pregnant.
For typical use, the rate is also 5 in 10,000.
Remember: If implantable hormones are your primary method, you must still use a secondary method at the
same time.
INJECTABLE HORMONES
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This method of birth control is a shot or needle injection of a hormone in your arm or buttocks, given to you by
your healthcare professional at specific intervals every 4 to 12 weeks. The hormone shot stops eggs from being
released, thickens vaginal mucus to keep the sperm from joining the egg and keeps a fertilized egg from
attaching to the womb.
Generally, the side effects are similar to those that occur if you take the Pill. This form of birth control is
reversible, but it may take several months after stopping the shots before you can become pregnant.
With perfect use, about 2-3 women in 1000 become pregnant.
For typical use, the rate is also 2-3 in 1000.
Injectable hormones can take up to 1 week to be fully effective; you can become pregnant during this week.
Patients who have certain illnesses, or a family history of some illnesses, may not be suited for this type of birth
control, so it is important to discuss these issues with your healthcare professional.
Remember: If injectable hormones are your primary method, you must still use a secondary method at the
same time.
THE INTRAUTERINE DEVICE (IUD)
The intrauterine device, which is called the IUD, is a plastic device that contains either copper or hormones.
Your healthcare professional puts the small plastic IUD in your womb. The copper or hormones in the IUD keep
the sperm from joining the egg and prevent a fertilized egg from attaching to the womb.
IUDs that contain hormones can be left in place for between 1 and 5 years. The copper-containing IUDs can be
left in place for up to 10 years. Side effects of all types of IUDs may include increased cramps and heavier and
longer periods. Women with new sex partners, women with more than one partner or women whose partners
have other partners have an increased chance of tubal infection (which may lead to sterility). These risks should
be discussed with your healthcare professional. He or she will also explain how to check the IUD for proper
position by feeling for a “tail” or string in the vagina. If the string cannot be felt, the IUD may have been
expelled or dislodged from its proper position and a healthcare professional should be consulted. This method
is not recommended for women who have not had a child.
With perfect use, about 1.5 women in 100 become pregnant.
For typical use, the rate is 2 in 100.
Remember: If an IUD is your primary method, you must still use a secondary method at the same time.
INSERTABLE HORMONES
The hormonal vaginal contraceptive ring is inserted by you into your vagina and contains a combination of
hormones similar to the Pill. After the ring is inserted, it releases a continuous low dose of hormones into your
body. The hormones stop the release of an egg and alter cervical mucus to keep sperm from entering the womb.
You leave it in for 3 weeks, and then you remove it for 1 week. During this time, your menstrual period will
begin. For your first cycle, the ring should be inserted between day 1 and day 5 of your menstrual period. It may
take up to 1 week to become fully effective in the first cycle.
Generally, the side effects are similar to those of the Pill. Other side effects may include vaginal discharge or
irritation. Like the Pill, the hormonal vaginal contraceptive ring may increase the risk of blood clots, heart attack
and stroke, especially in women who smoke. It should not be used by women with certain types of cancer or
other medical conditions, so it is important to discuss these issues with your prescriber.
With perfect use, about 7-8 women in 1000 become pregnant.
For typical use, the rate is 1-2 in 100.
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Remember: If the hormonal vaginal contraceptive ring is your primary method, you must still use a
secondary method at the same time. You cannot use the diaphragm as a secondary method because the
vaginal contraceptive ring may interfere with correct placement and position of a diaphragm.
STERILIZATION: TUBAL LIGATION AND VASECTOMY
Sterilization of either a man or woman requires an operation. A tubal tying (ligation) is intended to permanently
block a woman’s tubes where the sperm joins with the egg. A vasectomy is intended to permanently block a
man’s semen duct that carries sperm. However, it takes 15 to 20 ejaculations after sterilization to clear sperm
from the man’s semen.
You may become pregnant if your male partner has not had 2 consecutive counts that show there are no sperm
in the seminal fluid.
There are no lasting side effects and sterilization has no effect on sexual pleasure. Mild bleeding or infection
may occur right after the procedure. Sterilization is intended to be permanent; reversing the operation is very
difficult and cannot be guaranteed.
With perfect use, about 5 women in 1000 (using female sterilization) or 1 woman in 1000 (using male
sterilization) become pregnant.
For typical use, the rates are 5 in 1000 (female) and 1.5 in 1000 (male).
Remember: If sterilization is your primary method, you must still use a secondary method at the same time.
Secondary (moderately effective) forms of birth control
CONDOM, DIAPHRAGM OR CERVICAL CAP
Each of these is called a “barrier” method of birth control. They are used with a special gel called a
spermicide. A spermicide is a substance that kills sperm. By itself, it is NOT an adequate birth control
method for Soriatane (acitretin) users. Spermicides come in several forms—creams, jellies, foams and
suppositories, which should be applied with your barrier method 10 to 30 minutes before each intercourse.
Spermicide must be applied each time you have sexual intercourse. Your contraception counselor should
explain to you exactly how to use the spermicide with the “barrier” method you choose. The barrier method,
plus the spermicide, only count as ONE of the 2 forms of effective birth control you must choose before
starting Soriatane. The diaphragm or cervical cap must be left in place for 6 hours after your last sexual act,
and a woman should not douche or rinse the vagina during this time.
You should understand exactly how to and how not to use barrier methods of birth control. You need to be
aware of common mistakes in their use that may result in pregnancy. These barrier methods of birth control are
considered less reliable than the other methods discussed earlier.
CONDOM
The condom, also called a “rubber,” is a thin sheath that traps the sperm. Condoms are made of latex, plastic or
animal tissue (natural skin). Condoms, when used properly and consistently, and with a spermicide, can be
effective in preventing pregnancy. It is also believed that latex condoms reduce the spread of some STDs
(sexually transmitted diseases), including HIV. Synthetic and natural skin condoms, or those made from the
skin of lamb’s intestines, are equally effective at preventing pregnancy. However, natural skin condoms do not
protect against STDs.
Proper use of a condom means several things. If you choose this method, it is important to have your
contraception counselor explain exactly how to follow these directions. The condom has to have been stored in a
cool, dry place and not exposed to heat or pressure. It should be rolled onto the erect penis before any contact
with the woman’s genitals. The rolled rim should always remain on the outside of the condom. If the condom
has been rolled incorrectly (backward), it should be discarded and replaced with a new one. A 1/2 inch of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 46
empty space should be left at the tip, but no air should be trapped. Air at the tip could cause the condom to
break.
The condom should be removed immediately after intercourse to prevent spillage of semen. A condom can be
used only once. Oil-based lubricants, like petroleum jelly and baby oil, should not be used with a condom.
Water-based lubricants are safe to use and will not destroy the condom. However, since it is necessary to use a
spermicide with a condom, this can be used as a lubricant. Care should be taken to avoid ripping, tearing or
slipping off during sexual activity.
With perfect use, about 3 women in 100 become pregnant.
For typical use, the rate is 14 in 100.
Remember: Condoms should never be used alone without a primary birth control method.
DIAPHRAGM
The diaphragm is a shallow latex cup. Its purpose is to cover the cervix and prevent sperm from passing up into
the womb. Because the size around the cervix varies from woman to woman, a diaphragm has to be custom fit
by a healthcare professional. The fit needs to be checked at least once every 2 years, if a weight gain or loss of 10
or more pounds occurs, or after pregnancy or an abortion.
The diaphragm can be inserted into the vagina up to 6 hours before sexual intercourse. Spermicide jelly or
cream is placed in the diaphragm and around the rim before insertion. Fresh spermicide should be applied with
each sexual intercourse or if 6 hours have elapsed before sexual intercourse occurs. The diaphragm should not
be removed when spermicide is reapplied. The diaphragm must be left in place for at least 6 hours after the last
sexual intercourse; it should not be left in place for longer than a total of 24 hours because of the risk of serious
infection (toxic shock syndrome). Once fitted, the diaphragm is inserted into the vagina so that the dome covers
the cervix and the rim fits snugly on the vaginal walls.
With perfect use (with spermicide), about 6 women in 100 become pregnant.
For typical use (with spermicide), the rate is 20 in 100.
Remember: A diaphragm should always be used with spermicide and only as a secondary method. A
separate primary method must always be used.
CERVICAL CAP
The cervical cap is a barrier method that must be individually fitted and prescribed by a healthcare provider.
The cervical cap is inserted by the female before each sexual intercourse and must be used in combination with
a spermicide to be considered moderately effective as a birth control method. The cervical cap is made of latex
and should never be used with an oil-based lubricant, such as petroleum jelly, as this will destroy the cap.
The cervical cap actually fits over the cervix. The cap should be left in place for at least 6 hours after the last
sexual intercourse, but not longer than 48 hours because of the risk of toxic shock syndrome. Spermicide is
placed in the cap before insertion, but it is best to add more spermicide with each intercourse while the cap is
still in place. The cervical cap should not be removed while the spermicide is being reapplied. Inserting and
removing the cervical cap can be somewhat more difficult than inserting and removing the diaphragm.
However, with sufficient instruction and practice, insertion and removal can usually be accomplished.
With perfect use, about 9 women in 100 become pregnant.
For typical use, the rate is 20 in 100.
Remember: A cervical cap should always be used with a spermicide and only as a secondary method. A
separate primary method must always be used.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 47
Other contraception methods
Do not use less effective methods of birth control such as birth control pills without estrogen, natural family
planning, fertility awareness or withdrawal while taking Soriatane (acitretin), a medication that can cause birth
defects to your unborn child. Ask your healthcare professional about other contraception methods that you may
use or have heard about.
Reference: 1. Trussell J, Card JJ, Rowland Hogue CJ. Adolescent sexual behavior, pregnancy, and childbearing.
In: Hatcher RA, Trussell J, Stewart F, et al, eds. Contraceptive Technology. 17th ed. New York, NY: Ardent Media,
Inc.; 1998:701-744.
[end of PPP booklet]
________________________________________________________________
Dear Prescriber/Pharmacist letter:
Dear Prescriber/Pharmacist:
Please be advised of the following important changes to the Soriatane (acitretin ) labeling.
The Soriatane Package Insert has been updated to provide additional information collected during the time the product has
been marketed. It has also been revised for ease of use. It is important to note the new Medication Guide for all patients
taking Soriatane, as well as changes to the informed consent form for female patients.
Prescribers and pharmacists are advised to read the entire Package Insert (enclosed) after reviewing the "Synopsis of
Informational Changes" below.
Synopsis of Informational Changes
•
The Soriatane "Patient Agreement/Informed Consent for Female Patients" has been revised for consistency with
the changes made in the Package Insert. After the prescriber has determined that a female patient may be a candidate
for Soriatane, and has explained the proper use of this medication, the patient should initial each of the 18 items and
sign and date the entire informed consent. This is an important component of the Pregnancy Prevention Program and is
included as part of the professional Package Insert.
•
To improve the communication regarding Soriatane to all healthcare providers, pharmacists and patients, Roche
Laboratories Inc. will be releasing a FDA approved Medication Guide (MedGuide) for Soriatane. This document
will be sent to prescribers’ offices and to all pharmacies in the United States to enhance the safe and effective use of
Soriatane.
The Medication Guide for Soriatane must be distributed by the pharmacist, as required by law, to every
Soriatane patient each time a Soriatane prescription is dispensed. The Medication Guide was developed in
conjunction with the FDA to emphasize key safety issues that patients should know about the use of Soriatane. The
Medication Guide for Soriatane summarizes, in simple language, the professional Package Insert, including the
approved indication for Soriatane, information about birth defects and pregnancy avoidance, and major adverse events.
The Medication Guide is a document required by the FDA for specific medications and must be available for every
patient. To reorder additional Soriatane Medication Guides, please call toll free 1-800-93-ROCHE. Soriatane is
supplied in 10 mg and 25 mg capsule strengths in bottles of 30. The Medication Guide is piggy backed onto the
Package Insert which is affixed to each bottle.
•
Informational Changes made to the Soriatane Package Insert are as follows:
•
The boxed CONTRAINDICATIONS AND WARNINGS SECTION has been changed as follows:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 48
Emphasizes the need for two effective forms of contraception (birth control) simultaneously . The
labeling now emphasizes that effective forms of contraception include both primary (tubal ligation, partner's
vasectomy, intrauterine devices, birth control pills, and injectable/implantable/insertable/topical hormonal
birth control products) and secondary forms (diaphragms, latex condoms, and cervical caps each used with a
spermicide). At least one of the two methods of birth control must be a primary form.
Data related to teratogenicity when Soriatane is taken by female and male patients have been updated,
clarified, and made more concise.
Patients should be cautioned not to self-medicate with the herbal supplement St. John's Wort because a
possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough
bleeding on oral contraceptives shortly after starting St. John's Wort.
Instructions for patients not to donate blood have been clarified and now appear both in the boxed
CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections of the Package Insert: "Patients
should not donate blood during Soriatane during and for at least 3 years following therapy because Soriatane
can cause birth defects and women of childbearing potential must not receive blood from patients being
treated with Soriatane".
•
A section entitled CLINICAL STUDIES has been added. This section presents the efficacy data from the two
pivotal clinical trials.
•
The first sentence of the INDICATIONS AND USAGE section has been amended. Instead of stating “Soriatane
is indicated for the treatment of severe psoriasis, including the erythrodermic and generalized pustular types, in
adults”, it now states “Soriatane is indicated for the treatment of severe psoriasis in adults”. This change is
consistent with the data in the CLINICAL STUDIES section.
•
The CONTRAINDICATIONS section has been revised. Soriatane is contraindicated in patients with severely
impaired liver and kidney function and in patients with chronic abnormally elevated blood lipid levels. The
combined use of Soriatane and methotrexate, and Soriatane and tetracyclines is contraindicated.
•
The following revisions and additions have been made to the WARNINGS section:
The internal black boxes around pancreatitis and pseudotumor cerebri have been removed, but these warnings
remain in the WARNINGS section. The internal black box for hepatoxicity remains. This change does not
reflect new safety information. It was made simply for labeling consistency with other serious adverse events.
Additional information has been added regarding Pancreatitis. There have been rare reports of pancreatitis
during Soriatane therapy in the absence of hypertriglyceridemia.
Additional instruction has been added regarding Hyperostosis. Periodic radiography of patients on Soriatane
treatment is warranted in the presence of symptoms or long-term use because the frequency and severity of
iatrogenic bony abnormality in adults is low.
Additional information has been added regarding Lipids and Possible Cardiovascular Effects. Although no
causal relationship has been established, there have been postmarketing reports of acute myocardial infarction
or thromboembolic events in patients on Soriatane therapy.
•
The following revisions and additions have been made to the PRECAUTIONS section:
The subsection "Nursing Mothers" has been updated to note that there is one prospective case report where
actitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive Soriatane
prior to or during nursing because of the potential for serious adverse reactions in nursing infants.
Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have
been reported. These events, including self-injurious behavior, have been reported in patients taking other
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 49
systemically administered retinoids as well as in patients taking Soriatane. Since other factors may have
contributed to these events, it is not known if they are related to Soriatane. Patients should be counseled to
stop taking Soriatane and notify their prescriber immediately if they experience psychiatric symptoms.
Decreased night vision has been reported with Soriatane therapy. Patients should be advised of this potential
problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be
carefully monitored.
Patients should not donate blood during Soriatane treatment and for at least 3 years following therapy
because Soriatane can cause birth defects and women of childbearing potential must not receive blood from
patients being treated with Soriatane.
The following language has been clarified to differentiate between non-medical and medically supervised
UV exposure: "Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical
ultraviolet exposure) because the effects are enhanced by retinoids)".
Prescribers should significantly lower doses of phototherapy when Soriatane is used because Soriatane-
induced effects on the stratum corneum can increase the risk of erythema (burning).
A Drug Interactions section has been reformatted for ease of reading and contains information about the
interactions between Soriatane and a) ethanol ; b) glibenclamide; c) information that microdosed progestin
preparations (minipills) may be an inadequate method of contraception during Soriatane therapy; d)
phenytoin.
The Pediatric Use section has been amended to include reports of decreases in bone mineral density in
children taking other systemic retinoids, including etretinate, a metabolite of Soriatane. A causal relationship
between effect on bone and Soriatane has not been established.
A Geriatric Use section has been added to note that clinical studies of Soriatane did not include sufficient
numbers of subjects aged 65 and over to determined whether they respond differently than younger subjects.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range.
•
The ADVERSE REACTIONS section which reports on the clinical trials experience has been reformatted for
your convenience to list the reported events by body system in alphabetical order. Additional adverse events are
reported in a newly created section Adverse Events/Postmarketing reports:
In addition to the events listed in the tables for the clinical trials, the following adverse events have been
identified during post-approval use of Soriatane. Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Cardiovascular - Acute myocardial infaction, thromboembolism, (see WARNINGS)stroke
Nervous System: Myopathy with peripheral neuropathy has been reported during Soriatane therapy.
Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events, including
self-injurious behavior, have been reported in patients taking other systemically administered retinoids as
well as in patients taking Soriatane. Since other factors may have contributed to these events, it is not
known if they are related to Soriatane. (see PRECAUTIONS).
Reproductive - Vulvovaginitis due to Candida albicans
Skin and appendages – Thinning of the skin, skin fragility and scaling may occur all over the body,
particularly on the palms and soles; nail fragility is frequently observed.
•
The OVERDOSAGE section has been amended to indicate that in the event of acute overdosage, Soriatane
must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A, ie, headache
and vertigo. Further instructions are provided regarding pregnancy testing and counseling for all female
patients of childbearing potential who have taken an overdose of Soriatane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-002
NDA 19-821/S-006
Page 50
•
The DOSAGE AND ADMINISTRATION section now addresses the fact that maintenance doses of 25 to
50 mg may be given (note: the previous Package Insert stated 25 or 50 mg). The section has been clarified to
note that maintenance doses be given dependent upon an individual patient’s response to initial treatment.
This section also notes that when Soriatane is used with phototherapy, the prescriber should decrease the
phototherapy dose, dependent on the patient's individual response.
Please refer to the enclosed complete updated product information for detailed information on Boxed Warnings,
Contraindications, Warnings, Precautions, Adverse Events, Overdosage, Dosage and Administration, Informed Consent,
and the Medication Guide.
If you have any questions about Soriatane, we encourage you to call the toll-free number for Roche at 1-800-526-6367.
Also, if you are aware of any serious Adverse Events potentially associated with the use of Soriatane, report such
information to Roche at the above number or to the Food and Drug Administration MedWatch program at 1-800-FDA-
1088.
Sincerely,
[End of Dear Professional Letter]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:00.136576
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019821s002s006lbl.pdf', 'application_number': 19821, 'submission_type': 'SUPPL ', 'submission_number': 2}
|
11,741
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NDA 19-821/S-014
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<Stiefel® logo>
SORIATANE®
(acitretin)
CAPSULES
<CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT logo>
Rx only
CONTRAINDICATIONS AND WARNINGS: Soriatane must not be used by females who are pregnant, or who
intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy.
Soriatane also must not be used by females who may not use reliable contraception while undergoing treatment and
for at least 3 years following discontinuation of treatment. Acitretin is a metabolite of etretinate (Tegison®), and
major human fetal abnormalities have been reported with the administration of acitretin and etretinate. Potentially,
any fetus exposed can be affected.
Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with the
formation of etretinate, which has a significantly longer elimination half-life than acitretin. Because the longer
elimination half-life of etretinate would increase the duration of teratogenic potential for female patients, ethanol
must not be ingested by female patients either during treatment with Soriatane or for 2 months after cessation of
therapy. This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate.
The mechanism of the metabolic process for conversion of acitretin to etretinate has not been fully defined. It is not
known whether substances other than ethanol are associated with transesterification.
Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of 0.6, 3 and
15 mg/kg, respectively. These doses are approximately 0.2, 0.3 and 3 times the maximum recommended therapeutic
dose, respectively, based on a mg/m2 comparison.
Major human fetal abnormalities associated with acitretin and/or etretinate administration have been reported
including meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactyly, absence of
terminal phalanges, malformations of hip, ankle and forearm, low-set ears, high palate, decreased cranial volume,
cardiovascular malformation and alterations of the skull and cervical vertebrae.
Soriatane should be prescribed only by those who have special competence in the diagnosis and treatment of severe
psoriasis, are experienced in the use of systemic retinoids, and understand the risk of teratogenicity.
Because of Soriatane's teratogenicity, a program called the Do Your
P.A.R.T program, Pregnancy Prevention Actively Required During and After Treatment, has been developed to
educate women of childbearing potential and their healthcare providers about the serious risks associated with
acitretin and to help prevent pregnancies from occurring with the use of this drug and for 3 years after its
discontinuation. The Do Your
P.A.R.T. program requirements are described below (see also PRECAUTIONS section).
Important Information for Women of Childbearing Potential:
Soriatane should be considered only for women with severe psoriasis unresponsive to other therapies or whose
clinical condition contraindicates the use of other treatments.
Females of reproductive potential must not be given a prescription for Soriatane until pregnancy is excluded.
Soriatane is contraindicated in females of reproductive potential unless the patient meets ALL of the following
conditions:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving
the initial Soriatane prescription. The first test (a screening test) is obtained by the prescriber when the decision is
made to pursue Soriatane therapy. The second pregnancy test (a confirmation test) should be done during the first 5
days of the menstrual period immediately preceding the beginning of Soriatane therapy. For patients with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-014
NDA 19-821/S-015
Page 4
amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse
(without using 2 effective forms of contraception [birth control] simultaneously).
• Must have a pregnancy test repeated every month during Soriatane treatment. The patient must have a negative
result from a urine or serum pregnancy test before receiving a Soriatane prescription. To encourage compliance
with this recommendation, a limited supply of the drug should be prescribed. For at least 3 years after
discontinuing Soriatane therapy, a pregnancy test must be repeated every 3 months.
• Must have selected and have committed to use 2 effective forms of contraception (birth control) simultaneously, at
least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has
undergone a hysterectomy or is clearly postmenopausal.
• Patients must use 2 effective forms of contraception (birth control) simultaneously for at least 1 month prior to
initiation of Soriatane therapy, during Soriatane therapy, and for at least 3 years after discontinuing Soriatane
therapy. A Soriatane Patient Referral Form is available so that patients can receive an initial free contraceptive
counseling session and pregnancy testing. Counseling about contraception and behaviors associated with an
increased risk of pregnancy must be repeated on a monthly basis by the prescriber during Soriatane therapy and
every 3 months for at least 3 years following discontinuation of Soriatane therapy.
Effective forms of contraception include both primary and secondary forms of contraception. Primary forms of
contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products. Secondary forms of contraception
include latex condoms (with or without spermicide), diaphragms and cervical caps (which must be used with a
spermicide).
Any birth control method can fail. Therefore, it is critically important that women of childbearing potential use 2
effective forms of contraception (birth control) simultaneously. It has not been established if there is a
pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established
that acitretin interferes with the contraceptive effect of microdosed progestin preparations.1 Microdosed “minipill”
progestin preparations are not recommended for use with Soriatane. It is not known whether other progestational
contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.
Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal
contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients
should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a
possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on
oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined
hormonal contraceptives who also used some form of St. John’s Wort (see PRECAUTIONS).
• Must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings about the
risk of potential birth defects if the fetus is exposed to Soriatane, about contraceptive failure, about the fact that they
must not ingest beverages or products containing ethanol while taking Soriatane and for 2 months after Soriatane
treatment has been discontinued, and about preventing pregnancy while taking Soriatane and for at least 3 years
after discontinuing Soriatane therapy.
If pregnancy does occur during Soriatane therapy or at any time for at least 3 years following discontinuation of
Soriatane therapy, the prescriber and patient should discuss the possible effects on the pregnancy. The available
information is as follows:
Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy. The risk of
severe fetal malformations is well established when systemic retinoids are taken during pregnancy. Pregnancy must
also be prevented after stopping acitretin therapy, while the drug is being eliminated to below a threshold blood
concentration that would be associated with an increased incidence of birth defects. Because this threshold has not
been established for acitretin in humans and because elimination rates vary among patients, the duration of
posttherapy contraception to achieve adequate elimination cannot be
calculated precisely. It is strongly recommended that contraception be continued for at least 3 years after stopping
treatment with acitretin, based on the following considerations:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-014
NDA 19-821/S-015
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• In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be eliminated
within 2 months, assuming a mean elimination half-life of 49 hours.
• In cases where etretinate is formed, as has been demonstrated with concomitant administration of acitretin and
ethanol,
♦ greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a
mean elimination half-life of 120 days.
♦ greater than 98% of the etretinate formed would be eliminated in 3 years, based on the
longest demonstrated elimination half-life of 168 days.
However, etretinate was found in plasma and subcutaneous fat in one patient reported to have had sporadic alcohol
intake, 52 months after she stopped acitretin therapy.2
• Severe birth defects have been reported where conception occurred during the time interval when the patient was
being treated with acitretin and/or etretinate. In addition, severe birth defects have also been reported when
conception occurred after the mother completed therapy. These cases have been reported both prospectively (before
the outcome was known) and retrospectively (after the outcome was known). The events below are listed without
distinction as to whether the reported birth defects are consistent with retinoid-induced embryopathy or not.
♦ There have been 318 prospectively reported cases involving pregnancies and the use of
etretinate, acitretin or both. In 238 of these cases, the conception occurred after the last
dose of etretinate (103 cases), acitretin (126) or both (9). Fetal outcome remained
unknown in approximately one-half of these cases, of which 62 were terminated and 14
were spontaneous abortions. Fetal outcome is known for the other 118 cases and 15 of the
outcomes were abnormal (including cases of absent hand/wrist, clubfoot, GI
malformation, hypocalcemia, hypotonia, limb malformation, neonatal apnea/anemia,
neonatal ichthyosis, placental disorder/death, undescended testicle and 5 cases of
premature birth). In the 126 prospectively reported cases where conception occurred
after the last dose of acitretin only, 43 cases involved conception at least 1 year but less
than 2 years after the last dose. There were 3 reports of abnormal outcomes out of these
43 cases (involving limb malformation, GI tract malformations and premature birth).
There were only 4 cases where conception occurred at least 2 years after the last dose but
there were no reports of birth defects in these cases.
♦ There is also a total of 35 retrospectively reported cases where conception occurred at
least one year after the last dose of etretinate, acitretin or both. From these cases there are
3 reports of birth defects when the conception occurred at least 1 year but less than 2
years after the last dose of acitretin (including heart malformations, Turner’s Syndrome,
and unspecified congenital malformations) and 4 reports of birth defects when conception
occurred 2 or more years after the last dose of acitretin (including foot malformation,
cardiac malformations [2 cases] and unspecified neonatal and infancy disorder). There
were 3 additional abnormal outcomes in cases where conception occurred 2 or more years
after the last dose of etretinate (including chromosome disorder, forearm aplasia, and
stillbirth).
♦ Females who have taken Tegison (etretinate) must continue to follow the contraceptive
recommendations for Tegison. Tegison is no longer marketed in the US; for information,
call Stiefel at 1-888-500-DERM (3376).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-014
NDA 19-821/S-015
Page 6
♦ Patients should not donate blood during and for at least 3 years following the completion
of Soriatane therapy because women of childbearing potential must not receive blood
from patients being treated with Soriatane.
Important Information For Males Taking Soriatane:
• Patients should not donate blood during and for at least 3 years following Soriatane therapy because women of
childbearing potential must not receive blood from patients being treated with Soriatane.
• Samples of seminal fluid from 3 male patients treated with acitretin and 6 male patients treated with etretinate
have been assayed for the presence of acitretin. The maximum concentration of acitretin observed in the seminal
fluid of these men was 12.5 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in
semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule. Thus, although it appears that residual
acitretin in seminal fluid poses little, if any, risk to a fetus while a male patient is taking the drug or after it is
discontinued, the no-effect limit for teratogenicity is unknown and there is no registry for birth defects associated
with acitretin. The available data are as follows:
There have been 25 cases of reported conception when the male partner was taking acitretin. The pregnancy
outcome is known in 13 of these 25 cases. Of these, 9 reports were retrospective and 4 were prospective (meaning the
pregnancy was reported prior to knowledge of the outcome)3.
Timing of Paternal
Acitretin Treatment
Relative to Conception
Delivery of
Healthy
Neonate
Spontaneous
Abortion
Induced
Abortion
Total
At time of conception
5*
5
1
11
Discontinued ~4 weeks prior
0
0
1**
1
Discontinued ~6 to 8 months prior
0
1
0
1
*Four of 5 cases were prospective.
**With malformation pattern not typical of retinoid embryopathy (bilateral cystic hygromas of neck, hypoplasia of lungs
bilateral, pulmonary atresia, VSD with overriding truncus arteriosus).
For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME
SORIATANE IS DISPENSED, AS REQUIRED BY LAW.
DESCRIPTION: Soriatane (acitretin), a retinoid, is available in 10 mg and 25 mg gelatin capsules for oral administration.
Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a
metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder
with a molecular weight of 326.44. The structural formula is:
Each capsule contains acitretin, microcrystalline cellulose, sodium ascorbate, gelatin, black monogramming ink and
maltodextrin (a mixture of polysaccharides).
Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide. They may also contain
benzyl alcohol, carboxymethylcellulose sodium, edetate calcium disodium.
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CLINICAL PHARMACOLOGY: The mechanism of action of Soriatane is unknown.
Pharmacokinetics: Absorption: Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was
given with food in all of the following studies. After administration of a single 50 mg oral dose of acitretin to 18 healthy
subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean 416 ng/mL) and were achieved in 2 to 5
hours (mean 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg.
Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was
given to 12 healthy subjects.
Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism (see Pharmacokinetic Drug Interactions: Ethanol): Following oral absorption, acitretin undergoes extensive
metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin
relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent
compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are
excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in
plasma are achieved within approximately 3 weeks.
Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the
feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose
administration is 49 hours (range 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range 28
to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
Special Populations: Psoriasis: In an 8-week study of acitretin pharmacokinetics in patients with psoriasis, mean steady-
state trough concentrations of acitretin increased in a dose proportional manner with dosages ranging from 10 to 50 mg
daily. Acitretin plasma concentrations were nonmeasurable (<4 ng/mL) in all patients 3 weeks after cessation of therapy.
Elderly: In a multiple-dose study in healthy young (n=6) and elderly (n=8) subjects, a two-fold increase in acitretin plasma
concentrations were seen in elderly subjects, although the elimination half-life did not change.
Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in end-stage renal failure subjects (n=6)
when compared to age-matched controls, following single 50 mg oral doses. Acitretin was not removed by hemodialysis in
these subjects.
Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS:
Drug Interactions): In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and
cimetidine, digoxin, phenprocoumon or glyburide.
Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed with
concurrent ingestion of acitretin and ethanol. In a two-way crossover study, all 10 subjects formed etretinate with
concurrent ingestion of a single 100 mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol,
approximately 1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range 22 to 105 ng/mL) was
observed, and extrapolation of AUC values indicated that the formation of etretinate in this study was comparable to a
single 5 mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100 mg oral dose of
acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent
ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93 evaluable psoriatic
patients on acitretin therapy in several foreign studies (10 to 80 mg/day), 16% had measurable etretinate levels (>5 ng/mL).
Etretinate has a much longer elimination half-life compared to that of acitretin. In one study the apparent mean terminal
half-life after 6 months of therapy was approximately 120 days (range 84 to 168 days). In another study of 47 patients
treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years
after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.
Progestin-only Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and
combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of
microdosed progestin preparations.1 Microdosed “minipill” progestin preparations are not recommended for use with
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-014
NDA 19-821/S-015
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Soriatane. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate
methods of contraception during acitretin therapy.
CLINICAL STUDIES: In two double-blind placebo controlled studies, Soriatane was administered once daily to patients
with severe psoriasis (ie, covering at least 10% to 20% of the body surface area). At 8 weeks (see Table 1) patients treated
in Study A with 50 mg Soriatane per day showed significant improvements (p ≤ 0.05) relative to baseline and to placebo in
the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In
study B, differences from baseline and from placebo were statistically significant (p ≤ 0.05) for all variables at both the 25
mg and 50 mg doses; it should be noted for Study B that no statistical adjustment for multiplicity was carried out.
Table 1. Summary of the Soriatane Efficacy Results of the 8-Week Double-Blind Phase of Studies A and B
Study A
Study B
Total daily dose
Total daily dose
Efficacy Variables
Placebo
(N=29)
50 mg
(N=29)
Placebo
(N=72)
25 mg
(N=74)
50 mg
(N=71)
Physician’s
Global Evaluation
Baseline
4.62
4.55
4.43
4.37
4.49
Mean Change
After 8 Weeks
−0.29
−2.00*
−0.06
−1.06*
−1.57*
Scaling
Baseline
4.10
3.76
3.97
4.11
4.10
Mean Change
After 8 Weeks
−0.22
−1.62*
−0.21
−1.50*
−1.78*
Thickness
Baseline
4.10
4.10
4.03
4.11
4.20
Mean Change
After 8 Weeks
−0.39
−2.10*
−0.18
−1.43*
−2.11*
Erythema
Baseline
4.21
4.59
4.42
4.24
4.45
Mean Change
After 8 Weeks
−0.33
−2.10*
−0.37
−1.12*
−1.65*
*Values were statistically significantly different from placebo and from baseline (p ≤ 0.05). No adjustment for
multiplicity was done for Study B.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s
global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of
the global assessments were made using a seven-point scale (0=none, 1=trace, 2=mild, 3=mild-moderate, 4=moderate,
5=moderate-severe, 6=severe).
A subset of 141 patients from both pivotal studies A and B continued to receive Soriatane in an open fashion for up to 24
weeks. At the end of the treatment period, all efficacy variables, as indicated in Table 2, were significantly improved (p ≤
0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity and physician’s global evaluation.
Table 2. Summary of the First Course of Soriatane Therapy (24 Weeks)
Variables
Study A
Study B
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Variables
Study A
Study B
Mean Total Daily Soriatane Dose (mg)
42.8
43.1
Mean Duration of Therapy (Weeks)
21.1
22.6
Physician’s Global Evaluation
N=39
N=98
Baseline
4.51
4.43
Mean Change From Baseline
−2.26*
−2.60*
Scaling
N=59
N=132
Baseline
3.97
4.07
Mean Change From Baseline
−2.15*
−2.42*
Thickness
N=59
N=132
Baseline
4.00
4.12
Mean Change From Baseline
−2.44*
−2.66*
Erythema
N=59
N=132
Baseline
4.35
4.33
Mean Change From Baseline
−2.31*
−2.29*
* Indicates that the difference from baseline was statistically significant (p ≤ 0.01).
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s
global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of
the global assessments were made using a seven-point scale (0=none, 1=trace, 2=mild, 3=mild-moderate, 4=moderate,
5=moderate-severe, 6=severe).
All efficacy variables improved significantly in a subset of 55 patients from Study A treated for a second, 6-month
maintenance course of therapy (for a total of 12 months of treatment); a small subset of patients (n=4) from Study A
continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).
INDICATIONS AND USAGE: Soriatane is indicated for the treatment of severe psoriasis in adults. Because of
significant adverse effects associated with its use, Soriatane should be prescribed only by those knowledgeable in the
systemic use of retinoids. In females of reproductive potential, Soriatane should be reserved for non-pregnant patients who
are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed
CONTRAINDICATIONS AND WARNINGS — Soriatane can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated,
have produced efficacy results similar to the initial course of therapy.
CONTRAINDICATIONS: Pregnancy Category X (see boxed CONTRAINDICATIONS AND WARNINGS).
Soriatane is contraindicated in patients with severely impaired liver or kidney function and in patients with chronic
abnormally elevated blood lipid values (see boxed WARNINGS: Hepatoxicity, WARNINGS: Lipids and Possible
Cardiovascular Effects, and PRECAUTIONS).
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently,
the combination of methotrexate with Soriatane is also contraindicated (see PRECAUTIONS: Drug Interactions).
Since both Soriatane and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see
WARNINGS: Pseudotumor Cerebri).
Soriatane is contraindicated in cases of hypersensitivity to the preparation (acitretin or excipients) or to other retinoids.
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WARNINGS: (see also boxed CONTRAINDICATIONS AND WARNINGS)
Hepatotoxicity: Of the 525 patients treated in US clinical trials, 2 had clinical jaundice with elevated serum bilirubin
and transaminases considered related to Soriatane treatment. Liver function test results in these patients returned
to normal after Soriatane was discontinued. Two of the 1289 patients treated in European clinical trials developed
biopsy-confirmed toxic hepatitis. A second biopsy in one of these patients revealed nodule formation suggestive of
cirrhosis. One patient in a Canadian clinical trial of 63 patients developed a three-fold increase of transaminases. A
liver biopsy of this patient showed mild lobular disarray, multifocal hepatocyte loss and mild triaditis of the portal
tracts compatible with acute reversible hepatic injury. The patient’s transaminase levels returned to normal 2
months after Soriatane was discontinued.
The potential of Soriatane therapy to induce hepatotoxicity was prospectively evaluated using liver biopsies in an
open-label study of 128 patients. Pretreatment and posttreatment biopsies were available for 87 patients. A
comparison of liver biopsy findings before and after therapy revealed 49 (58%) patients showed no change, 21
(25%) improved and 14 (17%) patients had a worsening of their liver biopsy status. For 6 patients, the classification
changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal
inflammation; both mild); for 7 patients, the change was from class I to class II (fatty infiltration, nuclear
variability, portal inflammation and focal necrosis; all moderate to severe); and for 1 patient, the change was from
class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result
abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found.
Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP) or LDH have occurred in approximately 1 in 3 patients
treated with Soriatane. Of the 525 patients treated in clinical trials in the US, treatment was discontinued in 20
(3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with Soriatane, the
drug should be discontinued and the etiology further investigated.
Ten of 652 patients treated in US clinical trials of etretinate, of which acitretin is the active metabolite, had clinical
or histologic hepatitis considered to be possibly or probably related to etretinate treatment. There have been reports
of hepatitis-related deaths worldwide; a few of these patients had received etretinate for a month or less before
presenting with hepatic symptoms or signs.
Hyperostosis: In adults receiving long-term treatment with Soriatane, appropriate examinations should be periodically
performed in view of possible ossification abnormalities (see ADVERSE REACTIONS). Because the frequency and
severity of iatrogenic bony abnormality in adults is low, periodic radiography is only warranted in the presence of
symptoms or long-term use of Soriatane. If such disorders arise, the continuation of therapy should be discussed with the
patient on the basis of a careful risk/benefit analysis. In clinical trials with Soriatane, patients were prospectively evaluated
for evidence of development or change in bony abnormalities of the vertebral column, knees and ankles.
Vertebral Results: Of 380 patients treated with Soriatane, 15% had preexisting abnormalities of the spine which showed
new changes or progression of preexisting findings. Changes included degenerative spurs, anterior bridging of spinal
vertebrae, diffuse idiopathic skeletal hyperostosis, ligament calcification and narrowing and destruction of a cervical disc
space. De novo changes (formation of small spurs) were seen in 3 patients after 1½ to 2½ years.
Skeletal Appendicular Results: Six of 128 patients treated with Soriatane showed abnormalities in the knees and ankles
before treatment that progressed during treatment. In 5, these changes involved the formation of additional spurs or
enlargement of existing spurs. The sixth patient had degenerative joint disease which worsened. No patients developed
spurs de novo. Clinical complaints did not predict radiographic changes.
Lipids and Possible Cardiovascular Effects: Blood lipid determinations should be performed before Soriatane is
administered and again at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8
weeks. In patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of patients. These effects of
Soriatane were generally reversible upon cessation of therapy.
Patients with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism,
diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions. Because of the risk of
hypertriglyceridemia, serum lipids must be more closely monitored in high-risk patients and during long-term treatment.
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Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status. Although no causal relationship
has been established, there have been postmarketing reports of acute myocardial infarction or thromboembolic events in
patients on Soriatane therapy. In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated
with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in Soriatane dose, or drug therapy should be
employed to control significant elevations of triglycerides. If, despite these measures, hypertriglyceridemia and low HDL
levels persist, the discontinuation of Soriatane should be considered.
Ophthalmologic Effects: The eyes and vision of 329 patients treated with Soriatane were examined by ophthalmologists.
The findings included dry eyes (23%), irritation of eyes (9%) and brow and lash loss (5%). The following were reported in
less than 5% of patients: Bell’s Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial
abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear cataract, pannus, papilledema,
photophobia, posterior subcapsular cataract, recurrent sties and subepithelial corneal lesions.
Any patient treated with Soriatane who is experiencing visual difficulties should discontinue the drug and undergo
ophthalmologic evaluation.
Pancreatitis: Lipid elevations occur in 25% to 50% of patients treated with Soriatane. Triglyceride increases sufficient to
be associated with pancreatitis are much less common, although fatal fulminant pancreatitis has been reported. There have
been rare reports of pancreatitis during Soriatane therapy in the absence of hypertriglyceridemia.
Pseudotumor Cerebri: Soriatane and other retinoids administered orally have been associated with cases of pseudotumor
cerebri (benign intracranial hypertension). Some of these events involved concomitant use of isotretinoin and tetracyclines.
However, the event seen in a single Soriatane patient was not associated with tetracycline use. Early signs and symptoms
include papilledema, headache, nausea and vomiting and visual disturbances. Patients with these signs and symptoms
should be examined for papilledema and, if present, should discontinue Soriatane immediately and be referred for
neurological evaluation and care. Since both Soriatane and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see CONTRAINDICATIONS).
PRECAUTIONS
A description of the Do Your P.A.R.T. materials is provided below. The main goals of the materials are to explain the
program requirements, to reinforce the educational messages, and to assess program effectiveness.
The Do Your P.A.R.T. booklet includes:
*
The Do Your P.A.R.T. Patient Brochure: information on the
program requirements, risks of acitretin, and the types of contraceptive
methods
*
The Contraceptive Counseling Referral Form for female patients
who want to receive free contraception counseling reimbursed by the
manufacturer
*
The Patient Agreement/Informed Consent Form for female patients
*
Medication Guide
The Do Your P.A.R.T. program also includes a voluntary patient
survey for women of childbearing potential to assess the effectiveness
of the Soriatane Pregnancy Prevention Program Do Your P.A.R.T.
Information for Patients (see Medication Guide for all patients and Patient Agreement/Informed Consent for Female
Patients at end of professional labeling):
Patients should be instructed to read the Medication Guide supplied as required by law when Soriatane is dispensed.
Females of reproductive potential: Soriatane can cause severe birth defects. Female patients must not be pregnant when
Soriatane therapy is initiated, they must not become pregnant while taking Soriatane, and for at least 3 years after stopping
Soriatane, so that the drug can be eliminated to below a blood concentration that would be associated with an increased
incidence of birth defects. Because this threshold has not been established for acitretin in humans and because elimination
rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated
precisely (see boxed CONTRAINDICATIONS AND WARNINGS).
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Females of reproductive potential should also be advised that they must not ingest beverages or products containing
ethanol while taking Soriatane and for 2 months after Soriatane treatment has been discontinued. This allows for
elimination of the acitretin which can be converted to etretinate in the presence of alcohol.
Female patients should be advised that any method of birth control can fail, including tubal ligation, and that microdosed
progestin “minipill” preparations are not recommended for use with Soriatane (see CLINICAL PHARMACOLOGY:
Pharmacokinetic Drug Interactions). Data from one patient who received a very low-dosed progestin contraceptive
(levonorgestrel 0.03 mg) had a significant increase of the progesterone level after three menstrual cycles during acitretin
treatment.2
Female patients should sign a consent form prior to beginning Soriatane therapy (see boxed CONTRAINDICATIONS
AND WARNINGS).
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case
report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive Soriatane
prior to or during nursing because of the potential for serious adverse reactions in nursing infants.
All Patients:
Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have been
reported. These events, including self-injurious behavior, have been reported in patients taking other systemically
administered retinoids, as well as in patients taking Soriatane. Since other factors may have contributed to these events, it is
not known if they are related to Soriatane. Patients should be counseled to stop taking Soriatane and notify their prescriber
immediately if they experience psychiatric symptoms.
Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period.
Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of Soriatane, although
some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials.
Decreased night vision has been reported with Soriatane therapy. Patients should be advised of this potential problem and
warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored (see
WARNINGS and ADVERSE REACTIONS). Patients should be advised that they may experience decreased tolerance to
contact lenses during the treatment period and sometimes after treatment has stopped.
Patients should not donate blood during and for at least 3 years following therapy because Soriatane can cause birth defects
and women of childbearing potential must not receive blood from patients being treated with Soriatane.
Because of the relationship of Soriatane to vitamin A, patients should be advised against taking vitamin A supplements in
excess of minimum recommended daily allowances to avoid possible additive toxic effects.
Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the
effects of UV light are enhanced by retinoids.
Patients should be advised that they must not give their Soriatane capsules to any other person.
For Prescribers:
Soriatane has not been studied in and is not indicated for treatment of acne.
Phototherapy: Significantly lower doses of phototherapy are required when Soriatane is used because Soriatane-induced
effects on the stratum corneum can increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).
Drug Interactions:
Ethanol: Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see
boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Glibenclamide: In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of
glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male
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volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of
diabetic patients under treatment with Soriatane is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics
and DOSAGE AND ADMINISTRATION).
Hormonal Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and
combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of
microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use
with Soriatane (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). It is not known whether other
progestational contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin
therapy.
Methotrexate: An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate.
Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS).
Phenytoin: If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.
Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is
contraindicated (see CONTRAINDICATIONS and WARNINGS: Pseudotumor Cerebri).
Vitamin A and oral retinoids: Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be
avoided because of the risk of hypervitaminosis A.
Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide.
Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed
no interaction.
Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring
or treatment discontinuation is recommended, depending on clinical judgment.
Blood Sugar: Some patients receiving retinoids have experienced problems with blood sugar control. In addition, new cases
of diabetes have been diagnosed during retinoid therapy, including diabetic ketoacidosis. In diabetics, blood-sugar levels
should be monitored very carefully.
Lipids: In clinical studies, the incidence of hypertriglyceridemia was 66%, hypercholesterolemia was 33% and that of
decreased HDL was 40%. Pretreatment and follow-up measurements should be obtained under fasting conditions. It is
recommended that these tests be performed weekly or every other week until the lipid response to Soriatane has stabilized
(see WARNINGS).
Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 patients
treated with Soriatane. It is recommended that these tests be performed prior to initiation of Soriatane therapy, at 1- to 2-
week intervals until stable and thereafter at intervals as clinically indicated (see CONTRAINDICATIONS and boxed
WARNINGS).
Carcinogenesis, Mutagenesis and Impairment of Fertility: Carcinogenesis: A carcinogenesis study of acitretin in Wistar
rats, at doses up to 2 mg/kg/day administered 7 days/week for 104 weeks, has been completed. There were no neoplastic
lesions observed that were considered to have been related to treatment with acitretin. An 80-week carcinogenesis study in
mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study
demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all
times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas
at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum
recommended human therapeutic dose based on a mg/m2 comparison.
Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT)
assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts and in an in vivo mouse
micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.
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Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of
acitretin tested, 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m2
comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest
and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day).
No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17
psoriatic patients, 8 patients with disorders of keratinization and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for
at least 12 weeks. In these studies, no deleterious effects were seen on either testosterone production, LH or FSH in any of
the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was
measured.4,5
Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed CONTRAINDICATIONS AND WARNINGS).
In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for 10 weeks (approximate
duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were
observed in the progeny (see boxed CONTRAINDICATIONS AND WARNINGS for information about male use of
Soriatane).
Nonteratogenic Effects: In rats dosed at 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose
based on a mg/m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest
dose tested, 1 mg/kg/day, no treatment-related adverse effects were observed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No clinical studies have been
conducted in pediatric patients. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses,
decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic
retinoids, including etretinate, a metabolite of Soriatane. A causal relationship between these effects and Soriatane has not
been established. While it is not known that these occurrences are more severe or more frequent in children, there is special
concern in pediatric patients because of the implications for growth potential (see WARNINGS: Hyperostosis).
Geriatric Use: Clinical studies of Soriatane did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy. A twofold increase in acitretin plasma concentrations was seen
in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL
PHARMACOLOGY: Special Populations).
ADVERSE REACTIONS: Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the
mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many of the clinical adverse
reactions reported to date with Soriatane administration resemble those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports: In addition to the events listed in the tables for the clinical trials, the following
adverse events have been identified during postapproval use of Soriatane. Because these events are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual
relationship to drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism (see WARNINGS), stroke
Nervous System: Myopathy with peripheral neuropathy has been reported during Soriatane therapy. Both conditions
improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events, including self-injurious
behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking
Soriatane. Since other factors may have contributed to these events, it is not known if they are related to Soriatane (see
PRECAUTIONS).
Reproductive: Vulvo-vaginitis due to Candida albicans
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Skin and Appendages: Thinning of the skin, skin fragility and scaling may occur all over the body, particularly on the palms
and soles; nail fragility is frequently observed.
Clinical Trials: During clinical trials with Soriatane, 513/525 (98%) of patients reported a total of 3545 adverse events.
One-hundred sixteen patients (22%) left studies prematurely, primarily because of adverse experiences involving the
mucous membranes and skin. Three patients died. Two of the deaths were not drug related (pancreatic adenocarcinoma and
lung cancer); the other patient died of an acute myocardial infarction, considered remotely related to drug therapy. In
clinical trials, Soriatane was associated with elevations in liver function test results or triglyceride levels and hepatitis.
The tables below list by body system and frequency the adverse events reported during clinical trials of 525 patients with
psoriasis.
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Table 3. Adverse Events Frequently Reported During Clinical Trials
Percent of Patients Reporting (N=525)
BODY SYSTEM
> 75%
50% to 75%
25% to 50%
10% to 25%
CNS
Rigors
Eye Disorders
Xerophthalmia
Mucous Membranes
Cheilitis
Rhinitis
Dry mouth
Epistaxis
Musculoskeletal
Arthralgia
Spinal hyperostosis
(progression of
existing lesions)
Skin and Appendages
Alopecia
Skin peeling
Dry skin
Nail disorder
Pruritus
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Table 4. Adverse Events Less Frequently Reported During Clinical Trials
(Some of Which May Bear No Relationship to Therapy)
Percent of Patients Reporting (N=525)
BODY SYSTEM
1% to 10%
< 1%
Body as a Whole
Anorexia
Edema
Fatigue
Hot flashes
Increased
appetite
Alcohol
intolerance
Dizziness
Fever
Influenza-like
symptoms
Malaise
Moniliasis
Muscle weakness
Weight increase
Cardiovascular
Flushing
Chest pain
Cyanosis
Increased
bleeding time
Intermittent
claudication
Peripheral
ischemia
CNS (also see
Psychiatric)
Headache
Pain
Abnormal gait
Migraine
Neuritis
Pseudotumor
cerebri
(intracranial
hypertension)
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BODY SYSTEM
1% to 10%
< 1%
Eye Disorders
Abnormal/
blurred vision
Blepharitis
Conjunctivitis/
irritation
Corneal epithelial
abnormality
Decreased night
vision/night
blindness
Eye abnormality
Eye pain
Photophobia
Abnormal
lacrimation
Chalazion
Conjunctival
hemorrhage
Corneal ulceration
Diplopia
Ectropion
Itchy eyes and lids
Papilledema
Recurrent sties
Subepithelial
corneal lesions
Gastrointestinal
Abdominal pain
Diarrhea
Nausea
Tongue disorder
Constipation
Dyspepsia
Esophagitis
Gastritis
Gastroenteritis
Glossitis
Hemorrhoids
Melena
Tenesmus
Tongue ulceration
Liver and Biliary
Hepatic function
abnormal
Hepatitis
Jaundice
Mucous Membranes
Gingival bleeding
Gingivitis
Increased saliva
Stomatitis
Thirst
Ulcerative
stomatitis
Altered saliva
Anal disorder
Gum hyperplasia
Hemorrhage
Pharyngitis
Musculoskeletal
Arthritis
Arthrosis
Back pain
Hypertonia
Myalgia
Osteodynia
Peripheral joint
hyperostosis
(progression of
existing lesions)
Bone disorder
Olecranon bursitis
Spinal hyperostosis
(new lesions)
Tendonitis
Psychiatric
Depression
Insomnia
Somnolence
Anxiety
Dysphonia
Libido decreased
Nervousness
Reproductive
Atrophic vaginitis
Leukorrhea
Respiratory
Sinusitis
Coughing
Increased sputum
Laryngitis
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BODY SYSTEM
1% to 10%
< 1%
Skin and Appendages
Abnormal skin
odor
Abnormal hair
texture
Bullous eruption
Cold/clammy
skin
Dermatitis
Increased
sweating
Infection
Psoriasiform rash
Purpura
Pyogenic
granuloma
Rash
Seborrhea
Skin fissures
Skin ulceration
Sunburn
Acne
Breast pain
Cyst
Eczema
Fungal infection
Furunculosis
Hair discoloration
Herpes simplex
Hyperkeratosis
Hypertrichosis
Hypoesthesia
Impaired healing
Otitis media
Otitis externa
Photosensitivity
reaction
Psoriasis aggravated
Scleroderma
Skin nodule
Skin hypertrophy
Skin disorder
Skin irritation
Sweat gland
disorder
Urticaria
Verrucae
Special Senses/ Other
Earache
Taste perversion
Tinnitus
Ceruminosis
Deafness
Taste loss
Urinary
Abnormal urine
Dysuria
Penis disorder
Laboratory: Soriatane therapy induces changes in liver function tests in a significant number of patients. Elevations of AST
(SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 patients treated with Soriatane. In most patients,
elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of
treatment. In patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient,
usually reversible elevations of alkaline phosphatase have been observed.
Table 5 lists the laboratory abnormalities reported during clinical trials.
Table 5. Abnormal Laboratory Test Results Reported During Clinical Trials
Percent of Patients Reporting
BODY SYSTEM
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Electrolytes
Increased:
–Phosphorus
–Potassium
–Sodium
Decreased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Magnesium
Increased and
decreased:
–Calcium
–Chloride
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BODY SYSTEM
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Hematologic
Increased:
–Reticulocytes
Decreased:
–Hematocrit
–Hemoglobin
–WBC
Increased:
–Haptoglobin
–Neutrophils
–WBC
Increased:
–Bands
–Basophils
–Eosinophils
–Hematocrit
–Hemoglobin
–Lymphocytes
–Monocytes
Decreased:
–Haptoglobin
–Lymphocytes
–Neutrophils
–Reticulocytes
Increased or
decreased:
–Platelets
–RBC
Hepatic
Increased:
–Cholesterol
–LDH
–SGOT
–SGPT
Decreased:
–HDL
cholesterol
Increased:
–Alkaline
phosphatase
–Direct bilirubin
–GGTP
Increased:
–Globulin
–Total bilirubin
–Total protein
Increased and
decreased:
–Serum albumin
Miscellaneous
Increased:
–Triglycerides
Increased:
–CPK
–Fasting blood
sugar
Decreased:
–Fasting blood
sugar
–High occult
blood
Increased and
decreased:
–Iron
Renal
Increased:
–Uric acid
Increased:
–BUN
–Creatinine
Urinary
WBC in urine
Acetonuria
Hematuria
RBC in urine
Glycosuria
Proteinuria
OVERDOSAGE: In the event of acute overdosage, Soriatane must be withdrawn at once. Symptoms of overdose are
identical to acute hypervitaminosis A, ie, headache and vertigo. The acute oral toxicity (LD50) of acitretin in both mice and
rats was greater than 4000 mg/kg.
In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25 mg capsules (525 mg single dose).
He vomited several hours later but experienced no other ill effects.
All female patients of childbearing potential who have taken an overdose of Soriatane must:
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1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed CONTRAINDICATIONS AND
WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after
the overdose.
DOSAGE AND ADMINISTRATION: There is intersubject variation in the pharmacokinetics, clinical efficacy and
incidence of side effects with Soriatane. A number of the more common side effects are dose related. Individualization of
dosage is required to achieve sufficient therapeutic response while minimizing side effects. Soriatane therapy should be
initiated at 25 to 50 mg per day, given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may
be given dependent upon an individual patient’s response to initial treatment. Relapses may be treated as outlined for initial
therapy.
When Soriatane is used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s
individual response (see PRECAUTIONS: General).
Females who have taken Tegison (etretinate) must continue to follow the contraceptive recommendations for
Tegison.
Information for Pharmacists: A Soriatane Medication Guide must be given to the patient each time Soriatane is dispensed,
as required by law.
HOW SUPPLIED: Brown and white capsules, 10 mg, imprinted SORIATANE 10 mg; bottles of 30 (NDC 63032-090-
25).
Brown and yellow capsules, 25 mg, imprinted SORIATANE 25 mg; bottles of 30 (NDC 63032-091-25).
Store between 15° and 25°C (59° and 77°F). Protect from light. Avoid exposure to high temperatures and humidity after the
bottle is opened.
REFERENCES:
1. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389. 2. Maier H, Honigsmann H: Concentration of etretinate in
plasma and subcutaneous fat after long-term acitretin. Lancet 348:1107, 1996. 3. Geiger JM, Walker M: Is there a
reproductive safety risk in male patients treated with acitretin (Neotigason®/Soriatane®)? Dermatology 205:105-107, 2002.
4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica 175:48-49, 1987. 5. Parsch EM,
et al.: Andrological investigation in men treated with acitretin (Ro 10-1670). Andrologia 22:479-482, 1990. 6. Kadar L, et
al.: Spermatological investigations in psoriatic patients treated with acitretin. In: Pharmacology of Retinoids in the Skin;
Reichert U. et al., ed, KARGER, Basel, vol. 3, pp 253-254, 1988.
PATIENT AGREEMENT/INFORMED CONSENT
FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber
CAUSES BIRTH DEFECTS/DO NOT GET PREGNANT<logo>
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each item. Do not sign this consent
and do not take SORIATANE® (acitretin) if there is anything that you do not understand.
_____________________________________________________________
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I am pregnant or become
pregnant while taking SORIATANE in any amount even for short periods of time. Birth defects have also happened in
babies of women who became pregnant after stopping SORIATANE treatment.
INITIAL: ___________
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2. I understand that I must not become pregnant while taking SORIATANE and for at least 3 years after the end of my
treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter products that contain
alcohol. I understand that the risk of birth defects may last longer than 3 years if I swallow any form of alcohol during
SORIATANE therapy, and for 2 months after I stop taking SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective forms of birth control at the same
time. The only exceptions are if I have had surgery to remove the womb (a hysterectomy) or my prescriber has told me I
have gone completely through menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at the same time for at least 1 month
before starting SORIATANE, for the entire time of SORIATANE therapy, and for at least 3 years after SORIATANE
treatment has stopped.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different methods at the same time, every
time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary: Tubal ligation (having
my tubes tied), partner’s vasectomy, birth control pills, injectable/implantable/insertable/topical (patch) hormonal
birth control products, and IUDs (intrauterine
devices). Secondary: Latex condoms (with or without spermicide, which is a special cream or jelly that kills
sperm), diaphragms and cervical caps (which must be used with a spermicide). I understand that at least 1 of my 2
methods of birth control must be a primary method.
INITIAL: ___________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to take during my SORIATANE
treatment because certain birth control methods may not work if I am taking certain medicines or herbal products (for
example, Saint John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely through menopause, I understand that I
must have 2 negative pregnancy test results before I can get a prescription to start SORIATANE. I will then have pregnancy
tests on a monthly basis during my SORIATANE therapy as instructed by my prescriber. In addition, for at least 3 years
after the end of my treatment with SORIATANE, I will have a pregnancy test every 3 months.
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not pregnant and have negative results
from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraceptive (birth control) counseling session and
pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during SORIATANE therapy and every 3 months for at least 3 years after stopping
Soriatane treatment that I should receive counseling from my prescriber about contraception (birth control) and behaviors
associated with an increased risk of pregnancy.
INITIAL: ___________
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14. I understand that I must stop taking SORIATANE right away and call my prescriber if I get pregnant, miss my
menstrual period, stop using birth control, or have sexual intercourse without using my 2 birth control methods during and
at least 3 years after stopping SORIATANE treatment.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of stopping SORIATANE, I understand
that I should report my pregnancy to Stiefel at 1-888-500-DERM (3376) or to the Food and Drug Administration (FDA)
MedWatch program at 1-800-FDA-1088. The information I share will be kept confidential (private) and will help the
company and the FDA evaluate the pregnancy prevention program to
prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T™ brochure. My prescriber has answered all my questions about
SORIATANE. I understand that it is my responsibility to follow my doctor’s instructions, and not to get pregnant
during SORIATANE treatment or for at least 3 years after I stop taking SORIATANE.
I now authorize my prescriber, ______________________________________________________, to begin my treatment
with SORIATANE.
Patient signature: ________________________________________
Date: ___________________
Parent/guardian signature (if under age 18): ____________________
Date: ___________________
Please print: Patient name and address: _______________________________________________________________
_______________________________________________________________
Telephone: _____________________________________________________________
I have fully explained to the patient, _________________________________________________, the nature and purpose
of the treatment described above and the risks to females of childbearing potential. I have asked the patient if she has any
questions regarding her treatment with SORIATANE and have answered those questions to the best of my ability.
Prescriber signature: _______________________________________
Date: __________________
MEDICATION GUIDE FOR PATIENTS
SORIATANE®
[sor-RYE-uh-tane]
(acitretin)
CAPSULES
Read this Medication Guide carefully before you start taking Soriatane and read it each time you get more Soriatane. There
may be new information.
The first information in this Guide is about birth defects and how to avoid pregnancy. After this section there is
important safety information about possible effects for any patient taking Soriatane. ALL patients should read this
entire Medication Guide carefully.
This information does not take the place of talking with your prescriber about your medical condition or treatment.
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What is the most important information I should know about Soriatane?
Soriatane can cause severe birth defects. If you are a female who can get pregnant, you should use Soriatane only if you
are not pregnant now, can avoid becoming pregnant for at least 3 years, and other medicines do not work for your severe
psoriasis or you cannot use other psoriasis medicines. Information about effects on unborn babies and about how to avoid
pregnancy is found in the next section: “What are the important warnings and instructions for females taking Soriatane?”.
CAUSES BIRTH DEFECTS <icon> DO NOT GET PREGNANT
What are the important warnings and instructions for females taking Soriatane?
• Before you receive your Soriatane prescription, you should have discussed and signed a Patient
Information/Consent form with your prescriber. This is to help make sure you understand the risk of birth defects
and how to avoid getting pregnant. If you did not talk to your prescriber about this and sign the form, contact
your prescriber.
• You must not take Soriatane if you are pregnant or might become pregnant during treatment or at any time for at
least 3 years after you stop treatment because Soriatane can cause severe birth defects.
• During Soriatane treatment and for 2 months after you stop Soriatane treatment, you must avoid drinks, foods,
and all medicines that contain alcohol. This includes over-the-counter products that contain alcohol. Avoiding
alcohol is very important, because alcohol changes Soriatane into a drug that may take longer than 3 years to leave your
body. The chance of birth defects may last longer than 3 years if you swallow any form of alcohol during Soriatane
therapy and for 2 months after you stop taking Soriatane.
• You and your prescriber must be sure you are not pregnant before you start Soriatane therapy. You must have
negative results from 2 pregnancy tests before you start Soriatane treatment. A negative result shows you are not
pregnant. Because it takes a few days after pregnancy begins for a test to show that you are pregnant, the first negative
test may not ensure you are not pregnant. Do not start Soriatane until you have negative results from 2 pregnancy tests.
• The first pregnancy test will be done at the time you and your prescriber decide if Soriatane might be right for
you.
• The second pregnancy test will usually be done during the first 5 days of your menstrual period, right before
you plan to start Soriatane. Your prescriber may suggest another time.
• After you start Soriatane therapy, you must have a pregnancy test repeated each month that you are taking Soriatane. This
is to be sure that you are not pregnant during treatment because Soriatane can cause birth defects.
• For at least 3 years after stopping Soriatane treatment, you must have a pregnancy test repeated every three months to
make sure that you are not pregnant.
• Discuss effective birth control (contraception) with your prescriber. You must use 2 effective forms of birth control
(contraception) at the same time during all of the following:
• for at least 1 month before beginning Soriatane treatment
• during treatment with Soriatane
• for at least 3 years after stopping Soriatane treatment
• If you are sexually active, you must use 2 effective forms of birth control (contraception) at the same time even if
you think you cannot become pregnant, unless 1 of the following is true for you:
•
You had your womb (uterus) removed during an operation (a hysterectomy).
•
Your prescriber said you have gone completely through menopause (the “change of life”).
• You can get a free birth control counseling session and pregnancy testing from a prescriber or family planning
expert. Your prescriber can give you a Soriatane Patient Referral Form for this free session.
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• You must use 2 effective forms of birth control (contraception) at the same time while you are on Soriatane
treatment. You must use birth control for at least 1 month before you start Soriatane, during treatment, and at
least 3 years after you stop Soriatane treatment.
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The following are considered effective forms of birth control:
Primary Forms:
• having your tubes tied (tubal ligation)
• partner’s vasectomy
• IUD (intrauterine device)
• birth control pills that contain both estrogen and progestin (combination
oral contraceptives)
• hormonal birth control products that are injected, implanted, or inserted in
your body
• birth control patch
Secondary Forms (use with a Primary Form):
• diaphragms with spermicide
• latex condoms (with or without spermicide)
• cervical caps with spermicide
At least 1 of your 2 methods of birth control must be a primary form.
• If you have sex at any time without using 2 effective forms of birth control (contraception) at the same time, or if
you get pregnant or miss your period, stop using Soriatane and call your prescriber right away.
• Consider “Emergency Contraception” (EC) if you have sex with a male without correctly using 2 effective forms of
birth control (contraception) at the same time. EC is also called “emergency birth control” or the “morning after” pill.
Contact your prescriber as soon as possible if you have sex without using 2 effective forms of birth control
(contraception) at the same time, because EC works best if it is used within 1 or 2 days after sex. EC is not a replacement
for your usual 2 effective forms of birth control (contraception) because it is not as effective as regular birth control
methods.
You can get EC from private doctors or nurse practitioners, women’s health centers, or hospital emergency rooms. You
can get the name and phone number of EC providers nearest you by calling the free Emergency Contraception Hotline at
1-888-NOT-2-LATE (1-888-668-2528).
• Stop taking Soriatane right away and contact your prescriber if you get pregnant while taking Soriatane or at any
time for at least 3 years after treatment has stopped. You need to discuss the possible effects on the unborn baby
with your prescriber.
• If you do become pregnant while taking Soriatane or at any time for at least 3 years after stopping Soriatane, you
should report your pregnancy to Stiefel Laboratories, Inc. at 1-888-500-DERM (3376) or directly to the Food and
Drug Administration (FDA) MedWatch program (1-800-FDA-1088). Your name will be kept in private
(confidential). The information you share will help the FDA and the manufacturer evaluate the Pregnancy Prevention
Program for Soriatane.
• Do not take Soriatane if you are breast feeding. Soriatane can pass into your milk and may harm your baby. You will
need to choose either to breast feed or take Soriatane, but not both.
What should males know before taking Soriatane?
Small amounts of Soriatane are found in the semen of males taking Soriatane. Based upon available information, it appears
that these small amounts of Soriatane in semen pose little, if any, risk to an unborn child while a male patient is taking the
drug or after it is discontinued. Discuss any concerns you have about this with your prescriber.
All patients should read the rest of this Medication Guide.
What is Soriatane?
Soriatane is a medicine used to treat severe forms of psoriasis in adults. Psoriasis is a skin disease that causes cells in the
outer layer of the skin to grow faster than normal and pile up on the skin’s surface. In the most common type of psoriasis,
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the skin becomes inflamed and produces red, thickened areas, often with silvery scales. Because Soriatane can have
serious side effects, you should talk with your prescriber about whether Soriatane’s possible benefits outweigh its possible
risks.
Soriatane may not work right away. You may have to wait 2 to 3 months before you get the full benefit of Soriatane.
Psoriasis gets worse for some patients when they first start Soriatane treatment.
Soriatane has not been studied in children.
Who should not take Soriatane?
• Do NOT take Soriatane if you can get pregnant. Do not take Soriatane if you are pregnant or might get pregnant during
Soriatane treatment or at any time for at least 3 years after you stop Soriatane treatment (see “What are the important
warnings and instructions for females taking Soriatane?”).
• Do NOT take Soriatane if you are breast feeding. Soriatane can pass into your milk and may harm your baby. You will
need to choose either to breast feed or take Soriatane, but not both.
• Do NOT take Soriatane if you have severe liver or kidney disease.
• Do NOT take Soriatane if you have repeated high blood lipids (fat in the blood).
• Do NOT take Soriatane if you take these medicines:
• methotrexate
• tetracyclines
The use of these medicines with Soriatane may cause serious side effects.
• Do NOT take Soriatane if you are allergic to acitretin, the active ingredient in Soriatane, to any of the other ingredients
(see the end of this Medication Guide for a list of all the ingredients in Soriatane), or to any similar drugs (ask your
prescriber or pharmacist whether any drugs you are allergic to are related to Soriatane).
Tell your prescriber if you have or ever had:
• diabetes or high blood sugar
• liver problems
• kidney problems
• high cholesterol or high triglycerides (fat in the blood)
• heart disease
• depression
• alcoholism
• an allergic reaction to a medication
Your prescriber needs this information to decide if Soriatane is right for you and to know what dose is best for you.
Tell your prescriber about all the medicines you take, including prescription and non-prescription medicines, vitamins,
and herbal supplements. Some medicines can cause serious side effects if taken while you also take Soriatane. Some
medicines may affect how Soriatane works, or Soriatane may affect how your other medicines work. Be especially sure to
tell your prescriber if you are taking the following medicines:
• methotrexate
• tetracyclines
• phenytoin
• vitamin A supplements
• progestin-only oral contraceptives (“minipills”)
• Tegison® or Tigason (etretinate). Tell your prescriber if you have ever taken this medicine in the past.
• St. John’s Wort herbal supplement
Tell your prescriber if you are getting phototherapy treatment. Your doses of phototherapy may need to be changed to
prevent a burn.
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NDA 19-821/S-014
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How should I take Soriatane?
• Take Soriatane with food.
• Be sure to take your medicine as prescribed by your prescriber. The dose of Soriatane varies from patient to patient. The
number of capsules you must take is chosen specially for you by your prescriber. This dose may change during treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose and resume your normal schedule.
• If you take too much Soriatane (overdose), call your local poison control center or emergency room.
You should have blood tests for liver function, cholesterol and triglycerides before starting treatment and during treatment
to check your body’s response to Soriatane. Your prescriber may also do other tests.
Once you stop taking Soriatane, your psoriasis may return. Do not treat this new psoriasis with leftover Soriatane. It is
important to see your prescriber again for treatment recommendations because your situation may have changed.
What should I avoid while taking Soriatane?
• Avoid pregnancy. See “What is the most important information I should know about Soriatane?”, and “What are the
important warnings and instructions for females taking Soriatane?”.
• Avoid breast feeding. See “What are the important warnings and instructions for females taking Soriatane?”
• Avoid alcohol. Females must avoid drinks, foods, medicines, and over-the-counter products that contain alcohol. The risk
of birth defects may continue for longer than 3 years if you swallow any form of alcohol during Soriatane treatment and
for 2 months after stopping Soriatane (see “What are the important warnings and instructions for females taking
Soriatane?”).
• Avoid giving blood. Do not donate blood while you are taking Soriatane and for at least 3 years after stopping
Soriatane treatment. Soriatane in your blood can harm an unborn baby if your blood is given to a pregnant woman.
Soriatane does not affect your ability to receive a blood transfusion.
• Avoid progestin-only birth control pills (“minipills”). This type of birth control pill may not work while you take
Soriatane. Ask your prescriber if you are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop taking Soriatane and call your prescriber if this
occurs (see “Serious side effects”).
• Avoid non-medical ultraviolet (UV) light. Soriatane can make your skin more sensitive to UV light. Do not use
sunlamps, and avoid sunlight as much as possible. If you are taking light treatment (phototherapy), your prescriber may
need to change your light dosages to avoid burns.
• Avoid dietary supplements containing vitamin A. Soriatane is related to vitamin A. Therefore, do not take supplements
containing vitamin A, because they may add to the unwanted effects of Soriatane. Check with your prescriber or
pharmacist if you have any questions about vitamin supplements.
• DO NOT SHARE Soriatane with anyone else, even if they have the same symptoms. Your medicine may harm them
or their unborn child.
What are the possible side effects of Soriatane?
• Soriatane can cause birth defects. See “What is the most important information I should know about Soriatane?” and
“What are the important warnings and instructions for females taking Soriatane?”
• Psoriasis gets worse for some patients when they first start Soriatane treatment. Some patients have more redness or
itching. If this happens, tell your prescriber. These symptoms usually get better as treatment continues, but your
prescriber may need to change the amount of your medicine.
Serious side effects. These do not happen often, but they can lead to permanent harm, or rarely, to death. Stop taking
Soriatane and call your prescriber right away if you get the following signs or symptoms:
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NDA 19-821/S-014
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• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be signs of increased brain pressure that can
lead to blindness or even death.
• Decreased vision in the dark (night blindness). Since this can start suddenly, you should be very careful when driving at
night. This problem usually goes away when Soriatane treatment stops. If you develop any vision problems or eye pain
stop taking Soriatane and call your prescriber.
• Depression. There have been some reports of patients developing mental problems including a depressed mood,
aggressive feelings, or thoughts of ending their own life (suicide). These events, including suicidal behavior, have been
reported in patients taking other drugs similar to Soriatane as well as patients taking Soriatane. Since other things may
have contributed to these problems, it is not known if they are related to Soriatane. It is very important to stop taking
Soriatane and call your prescriber right away if you develop such problems.
• Yellowing of your skin or the whites of your eyes, nausea and vomiting, loss of appetite, or dark urine. These can be
signs of serious liver damage.
• Aches or pains in your bones, joints, muscles, or back; trouble moving; loss of feeling in your hands or feet. These
can be signs of abnormal changes to your bones or muscles.
• Frequent urination, great thirst or hunger. Soriatane can affect blood sugar control, even if you do not already have
diabetes. These are some of the signs of high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble speaking, or swelling of a leg. These may be
signs of a heart attack, blood clots, or stroke. Soriatane can cause serious changes in blood fats (lipids). It is possible
for these changes to cause blood vessel blockages that lead to heart attacks, strokes, or blood clots.
Common side effects. If you develop any of these side effects or any unusual reaction, check with your prescriber to find
out if you need to change the amount of Soriatane you take. These side effects usually get better if the Soriatane dose is
reduced or Soriatane is stopped.
• Chapped lips; peeling fingertips, palms, and soles; itching; scaly skin all over; weak nails; sticky or fragile (weak)
skin; runny or dry nose, or nosebleeds. Your prescriber or pharmacist can recommend a lotion or cream to help treat
drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
• Hair loss. Most patients have some hair loss, but this condition varies among patients. No one can tell if you will lose
hair, how much hair you may lose or if and when it may grow back.
• Dry eyes. Soriatane may dry your eyes. Wearing contact lenses may be uncomfortable during and after treatment with
Soriatane because of the dry feeling in your eyes. If this happens, remove your contact lenses and call your prescriber.
Also read the section about vision under “Serious side effects”.
• Rise in blood fats (lipids). Soriatane can cause your blood fats (lipids) to rise. Most of the time this is not serious. But
sometimes the increase can become a serious problem (see information under “Serious side effects”). You should have
blood tests as directed by your prescriber.
These are not all the possible side effects of Soriatane. For more information, ask your prescriber or pharmacist.
How should I store Soriatane?
Keep Soriatane away from sunlight, high temperature, and humidity. Keep Soriatane away from children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-821/S-014
NDA 19-821/S-015
Page 29
What are the ingredients in Soriatane?
Active ingredient: acitretin
Inactive ingredients: microcrystalline cellulose, sodium ascorbate, gelatin, black monogramming ink and maltodextrin (a
mixture of polysaccharides). Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium
dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium disodium.
General information about the safe and effective use of Soriatane
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Soriatane for a
condition for which it was not prescribed. Do not give Soriatane to other people, even if they have the same symptoms that
you have.
This Medication Guide summarizes the most important information about Soriatane. If you would like more information,
talk with your prescriber. You can ask your pharmacist or prescriber for information about Soriatane that is written for
health professionals.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Tegison® is a registered trademark of Hoffmann-La Roche Inc.
Do Your P.A.R.T. is a trademark, and SORIATANE and Stiefel are registered trademarks, owned by Stiefel Laboratories,
Inc.
©2007 Stiefel Laboratories, Inc.
<Stiefel logo>
Manufactured for
Stiefel Laboratories, Inc.
Coral Gables, FL 33134
October 2007 <commodity number>
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:00.296003
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019821s014s015lbl.pdf', 'application_number': 19821, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
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NDA 019821/S-022
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SORIATANE®
(acitretin)
Capsules Do not get pregnant graphic
CONTRAINDICTIONS AND WARNINGS: Pregnancy
SORIATANE must not be used by females who are pregnant, or who intend to become
pregnant during therapy or at any time for at least 3 years following discontinuation of
therapy. SORIATANE also must not be used by females who may not use reliable
contraception while undergoing treatment and for at least 3 years following
discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON®), and
major human fetal abnormalities have been reported with the administration of acitretin
and etretinate. Potentially, any fetus exposed can be affected.
Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been
associated with the formation of etretinate, which has a significantly longer elimination
half-life than acitretin. Because the longer elimination half-life of etretinate would increase
the duration of teratogenic potential for female patients, ethanol must not be ingested by
female patients either during treatment with SORIATANE or for 2 months after cessation
of therapy. This allows for elimination of acitretin, thus removing the substrate for
transesterification to etretinate. The mechanism of the metabolic process for conversion of
acitretin to etretinate has not been fully defined. It is not known whether substances other
than ethanol are associated with transesterification.
Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats
at oral doses of 0.6, 3, and 15 mg/kg, respectively. These doses are approximately 0.2, 0.3,
and 3 times the maximum recommended therapeutic dose, respectively, based on a mg/m2
comparison.
Major human fetal abnormalities associated with acitretin and/or etretinate
administration have been reported including meningomyelocele; meningoencephalocele;
multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges;
malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial
volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae.
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SORIATANE should be prescribed only by those who have special competence in the
diagnosis and treatment of severe psoriasis, are experienced in the use of systemic
retinoids, and understand the risk of teratogenicity.
Because of the teratogenicity of SORIATANE, a program called the Do Your P.A.R.T
program, Pregnancy Prevention Actively Required During and After Treatment, has been
developed to educate women of childbearing potential and their healthcare providers about
the serious risks associated with acitretin and to help prevent pregnancies from occurring
with the use of this drug and for 3 years after its discontinuation. The Do Your P.A.R.T.
program requirements are described below and program materials are available at
www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784
3335 (1-888-STIEFEL) (see also PRECAUTIONS section).
Important Information for Women of Childbearing Potential:
SORIATANE should be considered only for women with severe psoriasis unresponsive
to other therapies or whose clinical condition contraindicates the use of other treatments.
Females of reproductive potential must not be given a prescription for SORIATANE
until pregnancy is excluded. SORIATANE is contraindicated in females of reproductive
potential unless the patient meets ALL of the following conditions:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at
least 25 mIU/mL before receiving the initial prescription for SORIATANE. The first
test (a screening test) is obtained by the prescriber when the decision is made to
pursue therapy with SORIATANE. The second pregnancy test (a confirmation test)
should be done during the first 5 days of the menstrual period immediately
preceding the beginning of therapy with SORIATANE. For patients with
amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception
[birth control] simultaneously).
• Must have a pregnancy test repeated every month during treatment with
SORIATANE. The patient must have a negative result from a urine or serum
pregnancy test before receiving a prescription for SORIATANE. To encourage
compliance with this recommendation, a limited supply of the drug should be
prescribed. For at least 3 years after discontinuing therapy with SORIATANE, a
pregnancy test must be repeated every 3 months.
• Must have selected and have committed to use 2 effective forms of contraception
(birth control) simultaneously, at least 1 of which must be a primary form, unless
absolute abstinence is the chosen method, or the patient has undergone a
hysterectomy or is clearly postmenopausal.
• Patients must use 2 effective forms of contraception (birth control) simultaneously
for at least 1 month prior to initiation of therapy with SORIATANE, during
therapy with SORIATANE, and for at least 3 years after discontinuing therapy with
Reference ID: 3455601
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SORIATANE. A SORIATANE Referral Form is available so that patients can
receive an initial free contraceptive counseling session and pregnancy testing.
Counseling about contraception and behaviors associated with an increased risk of
pregnancy must be repeated on a monthly basis by the prescriber during therapy
with SORIATANE and every 3 months for at least 3 years following discontinuation
of SORIATANE.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products.
Secondary forms of contraception include latex condoms (with or without
spermicide), diaphragms and cervical caps (which must be used with a spermicide).
Any birth control method can fail. Therefore, it is critically important that women
of childbearing potential use 2 effective forms of contraception (birth control)
simultaneously. It has not been established if there is a pharmacokinetic interaction
between acitretin and combined oral contraceptives. However, it has been
established that acitretin interferes with the contraceptive effect of microdosed
progestin preparations.1 Microdosed “minipill” progestin preparations are not
recommended for use with SORIATANE. It is not known whether other
progestational contraceptives, such as implants and injectables, are adequate methods
of contraception during acitretin therapy. Prescribers are advised to consult the
package insert of any medication administered concomitantly with hormonal
contraceptives, since some medications may decrease the effectiveness of these birth
control products. Patients should be prospectively cautioned not to self-medicate
with the herbal supplement St. John’s wort because a possible interaction has been
suggested with hormonal contraceptives based on reports of breakthrough bleeding
on oral contraceptives shortly after starting St. John’s wort. Pregnancies have been
reported by users of combined hormonal contraceptives who also used some form of
St. John’s wort (see PRECAUTIONS).
• Must have signed a Patient Agreement/Informed Consent for Female Patients that
contains warnings about the risk of potential birth defects if the fetus is exposed to
SORIATANE, about contraceptive failure, about the fact that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2
months after SORIATANE treatment has been discontinued, and about preventing
pregnancy while taking SORIATANE and for at least 3 years after discontinuing
SORIATANE.
If pregnancy does occur during therapy with SORIATANE or at any time for at
least 3 years following discontinuation of SORIATANE, the prescriber and patient
should discuss the possible effects on the pregnancy. The available information is as
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follows:
Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated
during pregnancy. The risk of severe fetal malformations is well established when
systemic retinoids are taken during pregnancy. Pregnancy must also be prevented
after stopping acitretin therapy, while the drug is being eliminated to below a
threshold blood concentration that would be associated with an increased incidence
of birth defects. Because this threshold has not been established for acitretin in
humans and because elimination rates vary among patients, the duration of
posttherapy contraception to achieve adequate elimination cannot be calculated
precisely. It is strongly recommended that contraception be continued for at least 3
years after stopping treatment with acitretin, based on the following considerations:
o In the absence of transesterification to form etretinate, greater than 98% of
the acitretin would be eliminated within 2 months, assuming a mean
elimination half-life of 49 hours.
o In cases where etretinate is formed, as has been demonstrated with
concomitant administration of acitretin and ethanol,
greater than 98% of the etretinate formed would be eliminated in 2 years,
assuming a mean elimination half-life of 120 days.
greater than 98% of the etretinate formed would be eliminated in 3 years, based
on the longest demonstrated elimination half-life of 168 days.
However, etretinate was found in plasma and subcutaneous fat in one patient
reported to have had sporadic alcohol intake, 52 months after she stopped
acitretin therapy.2
• Severe birth defects have been reported where conception occurred during the time
interval when the patient was being treated with acitretin and/or etretinate. In
addition, severe birth defects have also been reported when conception occurred
after the mother completed therapy. These cases have been reported both
prospectively (before the outcome was known) and retrospectively (after the
outcome was known). The events below are listed without distinction as to whether
the reported birth defects are consistent with retinoid-induced embryopathy or not.
Reference ID: 3455601
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There have been 318 prospectively reported cases involving pregnancies and the
use of etretinate, acitretin, or both. In 238 of these cases, the conception
occurred after the last dose of etretinate (103 cases), acitretin (126), or both (9).
Fetal outcome remained unknown in approximately one-half of these cases, of
which 62 were terminated and 14 were spontaneous abortions. Fetal outcome is
known for the other 118 cases and 15 of the outcomes were abnormal (including
cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia,
limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental
disorder/death, undescended testicle, and 5 cases of premature birth). In the 126
prospectively reported cases where conception occurred after the last dose of
acitretin only, 43 cases involved conception at least 1 year but less than 2 years
after the last dose. There were 3 reports of abnormal outcomes out of these 43
cases (involving limb malformation, GI tract malformations, and premature
birth). There were only 4 cases where conception occurred at least 2 years after
the last dose but there were no reports of birth defects in these cases.
There is also a total of 35 retrospectively reported cases where conception
occurred at least 1 year after the last dose of etretinate, acitretin, or both. From
these cases there are 3 reports of birth defects when the conception occurred at
least 1 year but less than 2 years after the last dose of acitretin (including heart
malformations, Turner’s Syndrome, and unspecified congenital malformations)
and 4 reports of birth defects when conception occurred 2 or more years after
the last dose of acitretin (including foot malformation, cardiac malformations [2
cases], and unspecified neonatal and infancy disorder). There were 3 additional
abnormal outcomes in cases where conception occurred 2 or more years after
the last dose of etretinate (including chromosome disorder, forearm aplasia, and
stillbirth).
Females who have taken TEGISON (etretinate) must continue to follow the
contraceptive recommendations for TEGISON. TEGISON is no longer
marketed in the US; for information, call Stiefel at 1-888-784-3335 (1-888
STIEFEL).
Patients should not donate blood during and for at least 3 years following the
completion of therapy with SORIATANE because women of childbearing
potential must not receive blood from patients being treated with SORIATANE.
Important Information For Males Taking SORIATANE:
Patients should not donate blood during and for at least 3 years following therapy
with SORIATANE because women of childbearing potential must not receive blood
from patients being treated with SORIATANE.
• Samples of seminal fluid from 3 male patients treated with acitretin and 6 male
patients treated with etretinate have been assayed for the presence of acitretin. The
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maximum concentration of acitretin observed in the seminal fluid of these men was
12.5 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug
transferred in semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule.
Thus, although it appears that residual acitretin in seminal fluid poses little, if any,
risk to a fetus while a male patient is taking the drug or after it is discontinued, the
no-effect limit for teratogenicity is unknown and there is no registry for birth
defects associated with acitretin. The available data are as follows:
There have been 25 cases of reported conception when the male partner was taking
acitretin. The pregnancy outcome is known in 13 of these 25 cases. Of these, 9 reports
were retrospective and 4 were prospective (meaning the pregnancy was reported prior to
knowledge of the outcome)3 .
Timing of Paternal
Acitretin Treatment
Relative to Conception
Delivery of
Healthy
Neonate
Spontaneous
Abortion
Induced
Abortion
Total
At time of conception
5a
5
1
11
Discontinued ~4 weeks prior
0
0
1b
1
Discontinued ~6 to 8 months prior
0
1
0
1
a Four of 5 cases were prospective.
b With malformation pattern not typical of retinoid embryopathy (bilateral cystic hygromas of
neck, hypoplasia of lungs bilateral, pulmonary atresia, VSD with overriding truncus arteriosus).
For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE
PATIENT EACH TIME SORIATANE IS DISPENSED, AS REQUIRED BY LAW.
DESCRIPTION:
SORIATANE (acitretin), a retinoid, is available in 10 mg, 17.5 mg, and 25 mg gelatin
capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6
trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is
related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder
with a molecular weight of 326.44. The structural formula is: structural formula
Each capsule contains acitretin, black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate.
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Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium
dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium
disodium.
CLINICAL PHARMACOLOGY
The mechanism of action of SORIATANE is unknown.
Pharmacokinetics: Absorption: Oral absorption of acitretin is optimal when given with
food. For this reason, acitretin was given with food in all of the following trials. After
administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma
concentrations ranged from 196 to 728 ng/mL (mean: 416 ng/mL) and were achieved in 2 to 5
hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with
increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the
administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy
subjects.
Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism: (See Pharmacokinetic Drug Interactions: Ethanol.) Following oral
absorption, acitretin undergoes extensive metabolism and interconversion by simple
isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent
compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both
parent compound and isomer are further metabolized into chain-shortened breakdown products
and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-
state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3
weeks.
Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin
are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal
elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to
96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157
hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
Special Populations: Psoriasis: In an 8-week trial of acitretin pharmacokinetics in
subjects with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose-
proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma
concentrations were nonmeasurable (<4 ng/mL) in all subjects 3 weeks after cessation of
therapy.
Elderly: In a multiple-dose trial in healthy young (n = 6) and elderly (n = 8) subjects, a
2-fold increase in acitretin plasma concentrations were seen in elderly subjects, although the
elimination half-life did not change.
Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in
subjects with end-stage renal failure (n = 6) when compared with age-matched controls,
following single 50 mg oral doses. Acitretin was not removed by hemodialysis in these subjects.
Reference ID: 3455601
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Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND
WARNINGS and PRECAUTIONS: Drug Interactions): In studies of in vivo
pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine,
digoxin, phenprocoumon, or glyburide.
Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-
life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way
crossover trial, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg oral
dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately
1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range: 22 to 105
ng/mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate
in this trial was comparable to a single 5 mg oral dose of etretinate. There was no detectable
formation of etretinate when a single 100 mg oral dose of acitretin was administered without
concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol
ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93
evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to 80 mg/day), 16%
had measurable etretinate levels (>5 ng/mL).
Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial
the apparent mean terminal half-life after 6 months of therapy was approximately 120 days
(range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had
detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was
discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.
Progestin-only Contraceptives: It has not been established if there is a
pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has
been established that acitretin interferes with the contraceptive effect of microdosed progestin
preparations.1 Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE. It is not known whether other progestational contraceptives, such as implants and
injectables, are adequate methods of contraception during acitretin therapy.
CLINICAL STUDIES
In 2 double-blind, placebo-controlled trials, SORIATANE was administered once daily to
subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8
weeks (see Table 1) subjects treated in Trial A with 50 mg of SORIATANE per day showed
significant improvements (P ≤0.05) relative to baseline and to placebo in the physician’s global
evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In
Trial B, differences from baseline and from placebo were statistically significant (P ≤0.05) for all
variables at both the 25 mg and 50 mg doses; it should be noted for Trial B that no statistical
adjustment for multiplicity was carried out.
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Table 1. Summary of the Efficacy Results of the 8-Week Double-Blind Phase of Trials A
and B of SORIATANE
Efficacy Variables
Trial A
Trial B
Total Daily Dose
Total Daily Dose
Placebo
(N = 29)
50 mg
(N = 29)
Placebo
(N = 72)
25 mg
(N = 74)
50 mg
(N = 71)
Physician’s
Global Evaluation
Baseline
Mean Change
After 8 Weeks
4.62
−0.29
4.55
−2.00a
4.43
−0.06
4.37
−1.06a
4.49
−1.57a
Scaling
Baseline
Mean Change
After 8 Weeks
4.10
−0.22
3.76
−1.62a
3.97
−0.21
4.11
−1.50a
4.10
−1.78a
Thickness
Baseline
Mean Change
After 8 Weeks
4.10
−0.39
4.10
−2.10 a
4.03
−0.18
4.11
−1.43 a
4.20
−2.11 a
Erythema
Baseline
Mean Change
After 8 Weeks
4.21
−0.33
4.59
−2.10a
4.42
−0.37
4.24
−1.12a
4.45
−1.65a
a Values were statistically significantly different from placebo and from baseline (P ≤0.05). No
adjustment for multiplicity was done for Trial B.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
A subset of 141 subjects from both pivotal Trials A and B continued to receive SORIATANE
in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables,
as indicated in Table 2, were significantly improved (P ≤0.01) from baseline, including extent of
psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.
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Table 2. Summary of the First Course of Therapy With SORIATANE (24 Weeks)
Variables
Trial A
Trial B
Mean Total Daily Dose of SORIATANE (mg)
42.8
43.1
Mean Duration of Therapy (Weeks)
21.1
22.6
Physician’s Global Evaluation
Baseline
Mean Change From Baseline
N = 39
4.51
−2.26a
N = 98
4.43
−2.60a
Scaling
Baseline
Mean Change From Baseline
N = 59
3.97
−2.15a
N = 132
4.07
−2.42a
Thickness
Baseline
Mean Change From Baseline
N = 59
4.00
−2.44 a
N = 132
4.12
−2.66 a
Erythema
Baseline
Mean Change From Baseline
N = 59
4.35
−2.31a
N = 132
4.33
−2.29a
a Indicates that the difference from baseline was statistically significant (P ≤0.01).
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated
for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a
small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course
of therapy (for a total of 18 months of treatment).
INDICATIONS AND USAGE
SORIATANE is indicated for the treatment of severe psoriasis in adults. Because of
significant adverse effects associated with its use, SORIATANE should be prescribed only by
those knowledgeable in the systemic use of retinoids. In females of reproductive potential,
SORIATANE should be reserved for non-pregnant patients who are unresponsive to other
therapies or whose clinical condition contraindicates the use of other treatments (see boxed
CONTRAINDICATIONS AND WARNINGS — SORIATANE can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses,
when clinically indicated, have produced efficacy results similar to the initial course of therapy.
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CONTRAINDICATIONS
Pregnancy Category X: (See boxed CONTRAINDICATIONS AND WARNINGS.)
SORIATANE is contraindicated in patients with severely impaired liver or kidney function
and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS:
Hepatotoxicity, WARNINGS: Lipids and Possible Cardiovascular Effects, and
PRECAUTIONS).
An increased risk of hepatitis has been reported to result from combined use of methotrexate
and etretinate. Consequently, the combination of methotrexate with SORIATANE is also
contraindicated (see PRECAUTIONS: Drug Interactions).
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri).
SORIATANE is contraindicated in cases of hypersensitivity to the preparation (acitretin or
excipients) or to other retinoids.
WARNINGS
(See also boxed CONTRAINDICATIONS AND WARNINGS.)
Hepatotoxicity: Of the 525 subjects treated in US clinical trials, 2 had clinical jaundice
with elevated serum bilirubin and transaminases considered related to treatment with
SORIATANE. Liver function test results in these subjects returned to normal after
SORIATANE was discontinued. Two of the 1,289 subjects treated in European clinical
trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects
revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial
of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject
showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal
tracts compatible with acute reversible hepatic injury. The subject's transaminase levels
returned to normal 2 months after SORIATANE was discontinued.
The potential of therapy with SORIATANE to induce hepatotoxicity was prospectively
evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and
posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings
before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%)
improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6
subjects, the classification changed from class 0 (no pathology) to class I (normal fatty
infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the
change was from class I to class II (fatty infiltration, nuclear variability, portal
inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was
from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found
between liver function test result abnormalities and the change in liver biopsy status, and
no cumulative dose relationship was found.
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Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in
approximately 1 in 3 subjects treated with SORIATANE. Of the 525 subjects treated in
clinical trials in the US, treatment was discontinued in 20 (3.8%) due to elevated liver
function test results. If hepatotoxicity is suspected during treatment with SORIATANE, the
drug should be discontinued and the etiology further investigated.
Ten of 652 subjects treated in US clinical trials of etretinate, of which acitretin is the
active metabolite, had clinical or histologic hepatitis considered to be possibly or probably
related to etretinate treatment.
There have been reports of hepatitis-related deaths worldwide; a few of these subjects
had received etretinate for a month or less before presenting with hepatic symptoms or
signs.
Hyperostosis: In adults receiving long-term treatment with SORIATANE, appropriate
examinations should be periodically performed in view of possible ossification abnormalities
(see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic bony
abnormality in adults is low, periodic radiography is only warranted in the presence of symptoms
or long-term use of SORIATANE. If such disorders arise, the continuation of therapy should be
discussed with the patient on the basis of a careful risk/benefit analysis. In clinical trials with
SORIATANE, subjects were prospectively evaluated for evidence of development or change in
bony abnormalities of the vertebral column, knees, and ankles.
Vertebral Results: Of 380 subjects treated with SORIATANE, 15% had preexisting
abnormalities of the spine which showed new changes or progression of preexisting findings.
Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic
skeletal hyperostosis, ligament calcification, and narrowing and destruction of a cervical disc
space. De novo changes (formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.
Skeletal Appendicular Results: Six of 128 subjects treated with SORIATANE showed
abnormalities in the knees and ankles before treatment that progressed during treatment. In 5,
these changes involved the formation of additional spurs or enlargement of existing spurs. The
sixth subject had degenerative joint disease which worsened. No subjects developed spurs de
novo. Clinical complaints did not predict radiographic changes.
Lipids and Possible Cardiovascular Effects: Blood lipid determinations should be
performed before SORIATANE is administered and again at intervals of 1 to 2 weeks until the
lipid response to the drug is established, usually within 4 to 8 weeks. In subjects receiving
SORIATANE during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of
subjects. These effects of SORIATANE were generally reversible upon cessation of therapy.
Subjects with an increased tendency to develop hypertriglyceridemia included those with
disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a
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familial history of these conditions. Because of the risk of hypertriglyceridemia, serum lipids
must be more closely monitored in high-risk patients and during long-term treatment.
Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status.
Although no causal relationship has been established, there have been postmarketing reports of
acute myocardial infarction or thromboembolic events in patients on therapy with SORIATANE.
In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated with
fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of SORIATANE,
or drug therapy should be employed to control significant elevations of triglycerides. If, despite
these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of
SORIATANE should be considered.
Ophthalmologic Effects: The eyes and vision of 329 subjects treated with SORIATANE
were examined by ophthalmologists. The findings included dry eyes (23%), irritation of eyes
(9%), and brow and lash loss (5%). The following were reported in less than 5% of patients:
Bell’s Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial
abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear
cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and
subepithelial corneal lesions.
Any patient treated with SORIATANE who is experiencing visual difficulties should
discontinue the drug and undergo ophthalmologic evaluation.
Pancreatitis: Lipid elevations occur in 25% to 50% of patients treated with SORIATANE.
Triglyceride increases sufficient to be associated with pancreatitis are much less common,
although fatal fulminant pancreatitis has been reported. There have been rare reports of
pancreatitis during therapy with SORIATANE in the absence of hypertriglyceridemia.
Pseudotumor Cerebri: SORIATANE and other retinoids administered orally have been
associated with cases of pseudotumor cerebri (benign intracranial hypertension). Some of these
events involved concomitant use of isotretinoin and tetracyclines. However, the event seen in a
single patient receiving SORIATANE was not associated with tetracycline use. Early signs and
symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Patients
with these signs and symptoms should be examined for papilledema and, if present, should
discontinue SORIATANE immediately and be referred for neurological evaluation and care.
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see CONTRAINDICATIONS).
PRECAUTIONS
A description of the Do Your P.A.R.T. materials is provided below. The main goals of the
materials are to explain the program requirements, to reinforce the educational messages, and to
assess program effectiveness.
The Do Your P.A.R.T. booklet includes:
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• The Do Your P.A.R.T. Patient Brochure: information on the program requirements, risks of
acitretin, and the types of contraceptive methods
• The Contraceptive Counseling Referral Form for female patients who want to receive free
contraception counseling reimbursed by the manufacturer
• The Patient Agreement/Informed Consent Form for female patients
• Medication Guide
The Do Your P.A.R.T. program also includes a voluntary patient survey for women of
childbearing potential to assess the effectiveness of the SORIATANE Pregnancy Prevention
Program Do Your P.A.R.T.
Do Your P.A.R.T. Program materials are available at www.soriatane.com/doyour-part
Program.html or may be requested by calling 1-888-784-3335 (1-888-STIEFEL).
Information for Patients:
(See Medication Guide for all patients and Patient Agreement/Informed Consent for
Female Patients at end of professional labeling.)
Patients should be instructed to read the Medication Guide supplied as required by law when
SORIATANE is dispensed.
Females of Reproductive Potential: SORIATANE can cause severe birth defects.
Female patients must not be pregnant when therapy with SORIATANE is initiated, they must not
become pregnant while taking SORIATANE and for at least 3 years after stopping
SORIATANE, so that the drug can be eliminated to below a blood concentration that would be
associated with an increased incidence of birth defects. Because this threshold has not been
established for acitretin in humans and because elimination rates vary among patients, the
duration of posttherapy contraception to achieve adequate elimination cannot be calculated
precisely (see boxed CONTRAINDICATIONS AND WARNINGS).
Females of reproductive potential should also be advised that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2 months
after SORIATANE has been discontinued. This allows for elimination of the acitretin which
can be converted to etretinate in the presence of alcohol.
Female patients should be advised that any method of birth control can fail, including tubal
ligation, and that microdosed progestin “minipill” preparations are not recommended for use
with SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions).
Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel
0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during
acitretin treatment.2
Female patients should sign a consent form prior to beginning therapy with SORIATANE (see
boxed CONTRAINDICATIONS AND WARNINGS).
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the
milk. There is one prospective case report where acitretin is reported to be excreted in human
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milk. Therefore, nursing mothers should not receive SORIATANE prior to or during nursing
because of the potential for serious adverse reactions in nursing infants.
All Patients: Depression and/or other psychiatric symptoms such as aggressive feelings
or thoughts of self-harm have been reported. These events, including self-injurious behavior,
have been reported in patients taking other systemically administered retinoids, as well as in
patients taking SORIATANE. Since other factors may have contributed to these events, it is not
known if they are related to SORIATANE. Patients should be counseled to stop taking
SORIATANE and notify their prescriber immediately if they experience psychiatric symptoms.
Patients should be advised that a transient worsening of psoriasis is sometimes seen during the
initial treatment period. Patients should be advised that they may have to wait 2 to 3 months
before they get the full benefit of SORIATANE, although some patients may achieve significant
improvements within the first 8 weeks of treatment as demonstrated in clinical trials.
Decreased night vision has been reported during therapy with SORIATANE. Patients should
be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night. Visual problems should be carefully monitored (see WARNINGS and
ADVERSE REACTIONS). Patients should be advised that they may experience decreased
tolerance to contact lenses during the treatment period and sometimes after treatment has
stopped.
Patients should not donate blood during and for at least 3 years following therapy because
SORIATANE can cause birth defects and women of childbearing potential must not receive
blood from patients being treated with SORIATANE.
Because of the relationship of SORIATANE to vitamin A, patients should be advised against
taking vitamin A supplements in excess of minimum recommended daily allowances to avoid
possible additive toxic effects.
Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical
UV exposure) because the effects of UV light are enhanced by retinoids.
Patients should be advised that they must not give their SORIATANE to any other person.
For Prescribers: SORIATANE has not been studied in and is not indicated for treatment of
acne.
Phototherapy: Significantly lower doses of phototherapy are required when
SORIATANE is used because effects on the stratum corneum induced by SORIATANE can
increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).
Drug Interactions: Ethanol: Clinical evidence has shown that etretinate can be formed with
concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND
WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Glyburide: In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood
glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7
subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not
detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under
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treatment with SORIATANE is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Hormonal Contraceptives: It has not been established if there is a pharmacokinetic
interaction between acitretin and combined oral contraceptives. However, it has been established
that acitretin interferes with the contraceptive effect of microdosed progestin “minipill”
preparations. Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). It is
not known whether other progestational contraceptives, such as implants and injectables, are
adequate methods of contraception during acitretin therapy.
Methotrexate: An increased risk of hepatitis has been reported to result from combined use
of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is
also contraindicated (see CONTRAINDICATIONS).
Phenytoin: If acitretin is given concurrently with phenytoin, the protein binding of
phenytoin may be reduced.
Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial
pressure, their combined use is contraindicated (see CONTRAINDICATIONS and
WARNINGS: Pseudotumor Cerebri).
Vitamin A and Oral Retinoids: Concomitant administration of vitamin A and/or other oral
retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.
Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine,
digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of
anticoagulants of the coumarin type (warfarin) revealed no interaction.
Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage
reduction with careful monitoring or treatment discontinuation is recommended, depending on
clinical judgment.
Blood Sugar: Some patients receiving retinoids have experienced problems with blood
sugar control. In addition, new cases of diabetes have been diagnosed during retinoid therapy,
including diabetic ketoacidosis. In diabetics, blood-sugar levels should be monitored very
carefully.
Lipids: In clinical trials, the incidence of hypertriglyceridemia was 66%,
hypercholesterolemia was 33%, and that of decreased HDL was 40%. Pretreatment and follow-
up measurements should be obtained under fasting conditions. It is recommended that these tests
be performed weekly or every other week until the lipid response to SORIATANE has stabilized
(see WARNINGS).
Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT), or LDH were
experienced by approximately 1 in 3 patients treated with SORIATANE. It is recommended that
these tests be performed prior to initiation of therapy with SORIATANE, at 1- to 2-week
intervals until stable, and thereafter at intervals as clinically indicated (see
CONTRAINDICATIONS and boxed WARNINGS).
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Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A
carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg/kg/day administered 7
days/week for 104 weeks, has been completed. There were no neoplastic lesions observed that
were considered to have been related to treatment with acitretin. An 80-week carcinogenesis
study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data
obtained during this study demonstrated that etretinate was metabolized to acitretin and that
blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study,
an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several
different sites) was noted in male, but not female, mice at doses approximately one-half the
maximum recommended human therapeutic dose based on a mg/m2 comparison.
Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the
Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat
hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of
mutagenicity of acitretin was demonstrated in any of these assays.
Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not
impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the
maximum recommended therapeutic dose based on a mg/m2 comparison). Chronic toxicity
studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and
appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day).
No decreases in sperm count or concentration and no changes in sperm motility or
morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of
keratinization, and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks.
In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in
any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any
of the 18 men where it was measured.4,5
Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed
CONTRAINDICATIONS AND WARNINGS).
In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for
10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with
untreated female rats, no teratogenic effects were observed in the progeny (see boxed
CONTRAINDICATIONS AND WARNINGS for information about male use of SORIATANE).
Nonteratogenic Effects: In rats dosed at 3 mg/kg/day (approximately one-half the
maximum recommended therapeutic dose based on a mg/m2 comparison), slightly decreased pup
survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg/kg/day, no
treatment-related adverse effects were observed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No
clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments
and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and
premature epiphyseal closure have been reported in children taking other systemic retinoids,
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including etretinate, a metabolite of SORIATANE. A causal relationship between these effects
and SORIATANE has not been established. While it is not known that these occurrences are
more severe or more frequent in children, there is special concern in pediatric patients because of
the implications for growth potential (see WARNINGS: Hyperostosis).
Geriatric Use: Clinical trials of SORIATANE did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently than younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger subjects. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in
acitretin plasma concentrations was seen in healthy elderly subjects compared with young
subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY:
Special Populations).
ADVERSE REACTIONS
Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the
mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many
of the clinical adverse reactions reported to date with administration of SORIATANE resemble
those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports: In addition to the events listed in the tables for
the clinical trials, the following adverse events have been identified during postapproval use of
SORIATANE. Because these events are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism (see WARNINGS),
stroke.
Nervous System: Myopathy with peripheral neuropathy has been reported during therapy
with SORIATANE. Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events,
including self-injurious behavior, have been reported in patients taking other systemically
administered retinoids, as well as in patients taking SORIATANE. Since other factors may have
contributed to these events, it is not known if they are related to SORIATANE (see
PRECAUTIONS).
Reproductive: Vulvo-vaginitis due to Candida albicans.
Skin and Appendages: Thinning of the skin, skin fragility, and scaling may occur all over
the body, particularly on the palms and soles; nail fragility is frequently observed.
Clinical Trials: During clinical trials with SORIATANE, 513/525 (98%) of subjects reported a
total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely,
primarily because of adverse experiences involving the mucous membranes and skin. Three
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subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung
cancer); the other subject died of an acute myocardial infarction, considered remotely related to
drug therapy. In clinical trials, SORIATANE was associated with elevations in liver function test
results or triglyceride levels and hepatitis.
The tables below list by body system and frequency the adverse events reported during
clinical trials of 525 subjects with psoriasis.
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Table 3. Adverse Events Frequently Reported During Clinical Trials
Percent of Subjects Reporting (N = 525)
Body System
>75%
50% to 75%
25% to 50%
10% to 25%
CNS
Rigors
Eye Disorders
Xerophthalmia
Mucous Membranes
Cheilitis
Rhinitis
Dry mouth
Epistaxis
Musculoskeletal
Arthralgia
Spinal hyperostosis
(progression of
existing lesions)
Skin and Appendages
Alopecia
Skin peeling
Dry skin
Nail disorder
Pruritus
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Table 4. Adverse Events Less Frequently Reported During Clinical Trials (Some of Which
May Bear No Relationship to Therapy)
Percent of Subjects Reporting (N = 525)
Body System
1% to 10%
<1%
Body as a Whole
Anorexia
Edema
Fatigue
Hot flashes
Increased appetite
Alcohol
intolerance
Dizziness
Fever
Influenza-like
symptoms
Malaise
Moniliasis
Muscle weakness
Weight increase
Cardiovascular
Flushing
Chest pain
Cyanosis
Increased
bleeding time
Intermittent
claudication
Peripheral
ischemia
CNS (also see
Psychiatric)
Headache
Pain
Abnormal gait
Migraine
Neuritis
Pseudotumor
cerebri
(intracranial
hypertension)
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Eye Disorders
Abnormal/
blurred vision
Blepharitis
Conjunctivitis/
irritation
Corneal epithelial
abnormality
Decreased night
vision/night
blindness
Eye abnormality
Eye pain
Photophobia
Abnormal
lacrimation
Chalazion
Conjunctival
hemorrhage
Corneal ulceration
Diplopia
Ectropion
Itchy eyes and lids
Papilledema
Recurrent sties
Subepithelial
corneal lesions
Gastrointestinal
Abdominal pain
Diarrhea
Nausea
Tongue disorder
Constipation
Dyspepsia
Esophagitis
Gastritis
Gastroenteritis
Glossitis
Hemorrhoids
Melena
Tenesmus
Tongue ulceration
Liver and Biliary
Hepatic function
abnormal
Hepatitis
Jaundice
Mucous Membranes Gingival bleeding
Gingivitis
Increased saliva
Stomatitis
Thirst
Ulcerative
stomatitis
Altered saliva
Anal disorder
Gum hyperplasia
Hemorrhage
Pharyngitis
Musculoskeletal
Arthritis
Arthrosis
Back pain
Hypertonia
Myalgia
Osteodynia
Peripheral joint
hyperostosis
(progression of
existing lesions)
Bone disorder
Olecranon bursitis
Spinal
hyperostosis
(new lesions)
Tendonitis
Psychiatric
Depression
Insomnia
Somnolence
Anxiety
Dysphonia
Libido decreased
Nervousness
Reproductive
Atrophic vaginitis
Leukorrhea
Respiratory
Sinusitis
Coughing
Increased sputum
Laryngitis
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Skin and
Appendages
Abnormal skin
odor
Abnormal hair
texture
Bullous eruption
Cold/clammy skin
Dermatitis
Increased
sweating
Infection
Psoriasiform rash
Purpura
Pyogenic
granuloma
Rash
Seborrhea
Skin fissures
Skin ulceration
Sunburn
Acne
Breast pain
Cyst
Eczema
Fungal infection
Furunculosis
Hair discoloration
Herpes simplex
Hyperkeratosis
Hypertrichosis
Hypoesthesia
Impaired healing
Otitis media
Otitis externa
Photosensitivity
reaction
Psoriasis
aggravated
Scleroderma
Skin nodule
Skin hypertrophy
Skin disorder
Skin irritation
Sweat gland
disorder
Urticaria
Verrucae
Special Senses/
Other
Earache
Taste perversion
Tinnitus
Ceruminosis
Deafness
Taste loss
Urinary
Abnormal urine
Dysuria
Penis disorder
Laboratory: Therapy with SORIATANE induces changes in liver function tests in a
significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were
experienced by approximately 1 in 3 subjects treated with SORIATANE. In most subjects,
elevations were slight to moderate and returned to normal either during continuation of therapy
or after cessation of treatment. In subjects receiving SORIATANE during clinical trials, 66% and
33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density
lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient, usually reversible elevations
of alkaline phosphatase have been observed.
Table 5 lists the laboratory abnormalities reported during clinical trials.
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Table 5. Abnormal Laboratory Test Results Reported During Clinical Trials
Percent of Subjects Reporting
Body System
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Electrolytes
Increased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Magnesium
Decreased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Calcium
–Chloride
Hematologic
Increased:
–Reticulocytes
Decreased:
–Hematocrit
–Hemoglobin
–WBC
Increased:
–Haptoglobin
–Neutrophils
–WBC
Increased:
–Bands
–Basophils
–Eosinophils
–Hematocrit
–Hemoglobin
–Lymphocytes
–Monocytes
Decreased:
–Haptoglobin
–Lymphocytes
–Neutrophils
–Reticulocytes
Increased or
decreased:
–Platelets
–RBC
Hepatic
Increased:
–Cholesterol
–LDH
–SGOT
–SGPT
Decreased:
–HDL cholesterol
Increased:
–Alkaline
phosphatase
–Direct bilirubin
–GGTP
Increased:
–Globulin
–Total bilirubin
–Total protein
Increased and
decreased:
–Serum albumin
Miscellaneous
Increased:
–Triglycerides
Increased:
–CPK
–Fasting blood
sugar
Decreased:
–Fasting blood
sugar
–High occult
blood
Increased and
decreased:
–Iron
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Renal
Increased:
–Uric acid
Increased:
–BUN
–Creatinine
Urinary
WBC in urine
Acetonuria
Hematuria
RBC in urine
Glycosuria
Proteinuria
OVERDOSAGE
In the event of acute overdosage, SORIATANE must be withdrawn at once. Symptoms of
overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral
toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg/kg.
In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25 mg
capsules (525 mg single dose). He vomited several hours later but experienced no other ill
effects.
All female patients of childbearing potential who have taken an overdose of SORIATANE
must:
1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed
CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth
defects and contraceptive use for at least 3 years’ duration after the overdose.
DOSAGE AND ADMINISTRATION
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side
effects with SORIATANE. A number of the more common side effects are dose-related.
Individualization of dosage is required to achieve sufficient therapeutic response while
minimizing side effects. Therapy with SORIATANE should be initiated at 25 to 50 mg per day,
given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be
given dependent upon an individual patient’s response to initial treatment. Relapses may be
treated as outlined for initial therapy.
When SORIATANE is used with phototherapy, the prescriber should decrease the
phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS:
General).
Females who have taken TEGISON (etretinate) must continue to follow the
contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the
US; for information, call Stiefel at 1-888-784-3335 (1-888-STIEFEL).
Information for Pharmacists: A SORIATANE Medication Guide must be given to the
patient each time SORIATANE is dispensed, as required by law.
HOW SUPPLIED:
Brown and white capsules, 10 mg, imprinted “A-10 mg”; bottles of 30 (NDC 0145-0090-25).
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Rich yellow capsules, 17.5 mg, imprinted “A-17.5 mg”; bottles of 30 (NDC 0145-3817-03).
Brown and yellow capsules, 25 mg, imprinted “A-25 mg”; bottles of 30 (NDC 0145-0091
25).
Store between 15° and 25°C (59° and 77°F). Protect from light. Avoid exposure to high
temperatures and humidity after the bottle is opened.
REFERENCES:
1. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389.
2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after
long-term acitretin. Lancet 348:1107, 1996.
3. Geiger JM, Walker M: Is there a reproductive safety risk in male patients treated with acitretin
(Neotigason®/ Soriatane ®)? Dermatology 205:105-107, 2002.
4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica
175:48-49, 1987.
5. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670).
Andrologia 22:479-482, 1990.
6. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin. In:
Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3, pp
253-254, 1988.
PATIENT AGREEMENT/INFORMED CONSENT FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber Do not get pregnant graphic
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each item.
Do not sign this consent and do not take SORIATANE® (acitretin) if there is anything that
you do not understand.
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects
if I am pregnant or become pregnant while taking SORIATANE in any amount even for short
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periods of time. Birth defects have also happened in babies of women who became pregnant after
stopping treatment with SORIATANE.
INITIAL: ___________
2. I understand that I must not become pregnant while taking SORIATANE and for at least 3
years after the end of my treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter
products that contain alcohol. I understand that the risk of birth defects may last longer than 3
years if I swallow any form of alcohol during therapy with SORIATANE, and for 2 months after
I stop taking SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective forms
of birth control at the same time. The only exceptions are if I have had surgery to remove the
womb (a hysterectomy) or my prescriber has told me I have gone completely through
menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at the same
time for at least one month before starting SORIATANE, for the entire time of therapy with
SORIATANE, and for at least 3 years after stopping SORIATANE.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different methods
at the same time, every time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary:
Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills,
injectable/implantable/insertable/topical (patch) hormonal birth control products, and
IUDs (intrauterine devices). Secondary: Latex condoms (with or without spermicide,
which is a special cream or jelly that kills sperm), diaphragms and cervical caps (which
must be used with a spermicide). I understand that at least 1 of my 2 methods of birth
control must be a primary method.
INITIAL: ___________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to take while
taking SORIATANE because certain birth control methods may not work if I am taking certain
medicines or herbal products (for example, St. John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely through
menopause, I understand that I must have 2 negative pregnancy test results before I can get a
prescription to start SORIATANE. I will then have pregnancy tests on a monthly basis during
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therapy with SORIATANE as instructed by my prescriber. In addition, for at least 3 years after I
stop taking SORIATANE, I will have a pregnancy test every 3 months.
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not
pregnant and have negative results from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraceptive (birth control)
counseling session and pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during therapy with SORIATANE and every 3 months
for at least 3 years after stopping SORIATANE that I should receive counseling from my
prescriber about contraception (birth control) and behaviors associated with an increased risk of
pregnancy.
INITIAL: ___________
14. I understand that I must stop taking SORIATANE right away and call my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without
using my 2 birth control methods during and at least 3 years after stopping SORIATANE.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of stopping
SORIATANE, I understand that I should report my pregnancy to Stiefel at 1-888-784-3335 (1
888-STIEFEL) or to the Food and Drug Administration (FDA) MedWatch program at 1-800
FDA-1088. The information I share will be kept confidential (private) and will help the company
and the FDA evaluate the pregnancy prevention program to prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T™ brochure. My prescriber has answered all
my questions about SORIATANE. I understand that it is my responsibility to follow my
doctor’s instructions, and not to get pregnant during treatment with SORIATANE or for
at least 3 years after I stop taking SORIATANE.
I now authorize my prescriber,
______________________________________________________, to begin my treatment with
SORIATANE.
Patient signature: ________________________________________
Date: ___________________
Parent/guardian signature (if under age 18): ____________________
Date: ___________________
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Please print: Patient name and address:
Telephone: _____________________________________________________________
I have fully explained to the patient,
_________________________________________________, the nature and purpose of the
treatment described above and the risks to females of childbearing potential. I have asked the
patient if she has any questions regarding her treatment with SORIATANE and have answered
those questions to the best of my ability.
Prescriber signature: _______________________________________
Date: __________________
Revised 02/2014
SRN:xxPI
MEDICATION GUIDE
SORIATANE® (sor-RYE-uh-tane)
(acitretin)
Capsules
Read this Medication Guide carefully before you start taking SORIATANE and read it
each time you get more SORIATANE. There may be new information.
The first information in this Guide is about birth defects and how to avoid
pregnancy. After this section there is important safety information about
possible effects for any patient taking SORIATANE. ALL patients should read
this entire Medication Guide carefully.
This information does not take the place of talking with your prescriber about your
medical condition or treatment.
What is the most important information I should know about SORIATANE?
SORIATANE can cause serious side effects, including:
1. SEVERE BIRTH DEFECTS. IF YOU ARE A FEMALE WHO CAN GET PREGNANT, YOU SHOULD USE
SORIATANE ONLY IF YOU ARE NOT PREGNANT NOW, CAN AVOID BECOMING PREGNANT FOR AT
LEAST 3 YEARS, AND OTHER MEDICINES DO NOT WORK FOR YOUR SEVERE PSORIASIS OR YOU
CANNOT USE OTHER PSORIASIS MEDICINES. INFORMATION ABOUT EFFECTS ON UNBORN BABIES
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AND ABOUT HOW TO AVOID PREGNANCY IS FOUND IN THE NEXT SECTION: “WHAT ARE THE
IMPORTANT WARNINGS AND INSTRUCTIONS FOR FEMALES TAKING SORIATANE?” Do not get pregnant graphic
2. Liver problems, including abnormal liver function tests and inflammation of
your liver (hepatitis). Your prescriber should do blood tests to check how your liver
is working before you start taking and during treatment with SORIATANE. Stop
taking SORIATANE and call your prescriber right away if you have any of the
following signs or symptoms of a serious liver problem:
yellowing of your skin or the whites of your eyes
nausea and vomiting
loss of appetite
dark urine
What are the important warnings and instructions for females taking
SORIATANE?
• Before you receive your first prescription for SORIATANE, you should
have discussed and signed a Patient Information/Consent form with
your prescriber. This is to help make sure you understand the risk of
birth defects and how to avoid getting pregnant. If you did not talk to
your prescriber about this and sign the form, contact your prescriber.
• You must not take SORIATANE if you are pregnant or might become
pregnant during treatment or at any time for at least 3 years after you
stop treatment because SORIATANE can cause severe birth defects.
• During treatment with SORIATANE and for 2 months after you stop
treatment with SORIATANE, you must avoid drinks, foods, and all
medicines that contain alcohol. This includes over-the-counter products
that contain alcohol. Avoiding alcohol is very important, because alcohol
changes SORIATANE into a drug that may take longer than 3 years to leave your
body. The chance of birth defects may last longer than 3 years if you swallow
any form of alcohol during treatment with SORIATANE and for 2 months after
you stop taking SORIATANE.
• You and your prescriber must be sure you are not pregnant before you
start therapy with SORIATANE. You must have negative results from 2
pregnancy tests before you start treatment with SORIATANE. A negative
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result shows you are not pregnant. Because it takes a few days after pregnancy
begins for a test to show that you are pregnant, the first negative test may not
ensure you are not pregnant. Do not start SORIATANE until you have negative
results from 2 pregnancy tests.
• The first pregnancy test will be done at the time you and your prescriber
decide if SORIATANE might be right for you.
• The second pregnancy test will usually be done during the first 5 days of
your menstrual period, right before you plan to start SORIATANE. Your
prescriber may suggest another time.
• After you start taking SORIATANE, you must have a pregnancy test repeated
each month that you are taking SORIATANE. This is to be sure that you are not
pregnant during treatment because SORIATANE can cause birth defects.
• For at least 3 years after stopping treatment with SORIATANE, you must have a
pregnancy test repeated every 3 months to make sure that you are not
pregnant.
• Discuss effective birth control (contraception) with your prescriber. You
must use 2 effective forms of birth control (contraception) at the same
time during all of the following:
o for at least 1 month before beginning treatment with SORIATANE
o during treatment with SORIATANE
o for at least 3 years after stopping treatment with SORIATANE
• If you are sexually active, you must use 2 effective forms of birth
control (contraception) at the same time even if you think you cannot
become pregnant, unless 1 of the following is true for you:
o You had your womb (uterus) removed during an operation (a
hysterectomy).
o Your prescriber said you have gone completely through menopause
(the “change of life”).
• You can get a free birth control counseling session and pregnancy
testing from a prescriber or family planning expert. Your prescriber can
give you a SORIATANE Patient Referral Form for this free session.
• You must use 2 effective forms of birth control (contraception) at the
same time while you are on treatment with SORIATANE. You must use
birth control for at least 1 month before you start taking SORIATANE,
during treatment, and at least 3 years after you stop treatment with
SORIATANE.
The following are considered effective forms of birth control:
Primary Forms:
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having your tubes tied (tubal ligation)
partner’s vasectomy
IUD (Intrauterine device)
birth control pills that contain both estrogen and progestin (combination oral
contraceptives)
hormonal birth control products that are injected, implanted, or inserted in
your body
birth control patch
Secondary Forms (use with a Primary Form):
diaphragms with spermicide
latex condoms (with or without spermicide)
cervical caps with spermicide
At least 1 of your 2 methods of birth control must be a primary form.
• If you have sex at any time without using 2 effective forms of birth
control (contraception) at the same time, or if you get pregnant or miss
your period, stop using SORIATANE and call your prescriber right away.
• Consider “Emergency Contraception” (EC) if you have sex with a male
without correctly using 2 effective forms of birth control
(contraception) at the same time. EC is also called “emergency birth control”
or the “morning after” pill. Contact your prescriber as soon as possible if you
have sex without using 2 effective forms of birth control (contraception) at the
same time, because EC works best if it is used within 1 or 2 days after sex. EC is
not a replacement for your usual 2 effective forms of birth control
(contraception) because it is not as effective as regular birth control methods.
You can get EC from private doctors or nurse practitioners, women’s health
centers, or hospital emergency rooms. You can get the name and phone number
of EC providers nearest you by calling the free Emergency Contraception Hotline
at 1-888-668-2528 (1-888-NOT-2-LATE).
• Stop taking SORIATANE right away and contact your prescriber if you
get pregnant while taking SORIATANE or at any time for at least 3 years
after treatment has stopped. You need to discuss the possible effects on
the unborn baby with your prescriber.
• If you do become pregnant while taking SORIATANE or at any time for
at least 3 years after stopping SORIATANE, you should report your
pregnancy to Stiefel Laboratories, Inc. at 1-888-784-3335 (1-888
STIEFEL) or directly to the Food and Drug Administration (FDA)
MedWatch program at 1-800-FDA-1088. Your name will be kept in private
(confidential). The information you share will help the FDA and the manufacturer
evaluate the Pregnancy Prevention Program for SORIATANE.
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• Do not take SORIATANE if you are breast feeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
What should males know before taking SORIATANE?
Small amounts of SORIATANE are found in the semen of males taking SORIATANE.
Based upon available information, it appears that these small amounts of
SORIATANE in semen pose little, if any, risk to an unborn child while a male patient
is taking the drug or after it is discontinued. Discuss any concerns you have about
this with your prescriber.
All patients should read the rest of this Medication Guide.
What is SORIATANE?
SORIATANE is a medicine used to treat severe forms of psoriasis in adults. Psoriasis
is a skin disease that causes cells in the outer layer of the skin to grow faster than
normal and pile up on the skin’s surface. In the most common type of psoriasis, the
skin becomes inflamed and produces red, thickened areas, often with silvery scales.
Because SORIATANE can have serious side effects, you should talk with your
prescriber about whether possible benefits of SORIATANE outweigh its possible
risks.
SORIATANE may not work right away. You may have to wait 2 to 3 months before
you get the full benefit of SORIATANE. Psoriasis gets worse for some patients when
they first start treatment with SORIATANE.
SORIATANE has not been studied in children.
Who should not take SORIATANE?
• Do NOT take SORIATANE if you can get pregnant. Do not take SORIATANE
if you are pregnant or might get pregnant during SORIATANE treatment or at
any time for at least 3 years after you stop SORIATANE treatment (see “What
are the important warnings and instructions for females taking SORIATANE?”).
• Do NOT take SORIATANE if you are breastfeeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
• Do NOT take SORIATANE if you have severe liver or kidney disease.
• Do NOT take SORIATANE if you have repeated high blood lipids (fat in
the blood).
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• Do NOT take SORIATANE if you take these medicines:
o methotrexate
o tetracyclines
The use of these medicines with SORIATANE may cause serious side effects.
• Do NOT take SORIATANE if you are allergic to acitretin, the active
ingredient in SORIATANE, to any of the other ingredients (see the end of this
Medication Guide for a list of all the ingredients in SORIATANE), or to any similar
medicines (ask your prescriber or pharmacist whether any medicines you are
allergic to are related to SORIATANE).
Tell your prescriber if you have or ever had:
• diabetes or high blood sugar
• liver problems
• kidney problems
• high cholesterol or high triglycerides (fat in the blood)
• heart disease
• depression
• alcoholism
• an allergic reaction to a medication
Your prescriber needs this information to decide if SORIATANE is right for you and
to know what dose is best for you.
Tell your prescriber about all the medicines you take, including prescription
and over-the-counter medicines, vitamins, and herbal supplements. Some
medicines can cause serious side effects if taken while you also take SORIATANE.
Some medicines may affect how SORIATANE works, or SORIATANE may affect how
your other medicines work. Be especially sure to tell your prescriber if you are
taking the following medicines:
• methotrexate
• tetracyclines
• glyburide
• phenytoin
• vitamin A supplements
• progestin-only oral contraceptives (“minipills”)
• TEGISON® or TIGASON (etretinate). Tell your prescriber if you have ever taken
this medicine in the past.
• St. John’s wort herbal supplement
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Tell your prescriber if you are getting phototherapy treatment. Your doses of
phototherapy may need to be changed to prevent a burn.
How should I take SORIATANE?
• Take SORIATANE with food.
• Be sure to take your medicine as prescribed by your prescriber. The dose of
SORIATANE varies from patient to patient. The number of capsules you must
take is chosen specially for you by your prescriber. This dose may change during
treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose and
resume your normal schedule.
• If you take too much SORIATANE (overdose), call your local poison control
center or emergency room.
You should have blood tests for liver function, cholesterol, and triglycerides before
starting treatment and during treatment to check your body’s response to
SORIATANE. Your prescriber may also do other tests.
Once you stop taking SORIATANE, your psoriasis may return. Do not treat this new
psoriasis with leftover SORIATANE. It is important to see your prescriber again for
treatment recommendations because your situation may have changed.
What should I avoid while taking SORIATANE?
• Avoid pregnancy. See “What is the most important information I should know
about SORIATANE?”, and “What are the important warnings and instructions for
females taking SORIATANE?”
• Avoid breastfeeding. See “What are the important warnings and instructions
for females taking SORIATANE?”.
• Avoid alcohol. Females must avoid drinks, foods, medicines, and over-the
counter products that contain alcohol. The risk of birth defects may continue for
longer than 3 years if you swallow any form of alcohol during treatment with
SORIATANE and for 2 months after stopping SORIATANE (see “What are the
important warnings and instructions for females taking SORIATANE?”).
• Avoid giving blood. Do not donate blood while you are taking SORIATANE
and for at least 3 years after stopping treatment with SORIATANE.
SORIATANE in your blood can harm an unborn baby if your blood is given to a
pregnant woman. SORIATANE does not affect your ability to receive a blood
transfusion.
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• Avoid progestin-only birth control pills (“minipills”). This type of birth
control pill may not work while you take SORIATANE. Ask your prescriber if you
are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop
taking SORIATANE and call your prescriber if this occurs (see “Serious side
effects”).
• Avoid non-medical ultraviolet (UV) light. SORIATANE can make your skin
more sensitive to UV light. Do not use sunlamps, and avoid sunlight as much as
possible. If you are taking light treatment (phototherapy), your prescriber may
need to change your light dosages to avoid burns.
• Avoid dietary supplements containing vitamin A. SORIATANE is related to
vitamin A. Therefore, do not take supplements containing vitamin A, because
they may add to the unwanted effects of SORIATANE. Check with your
prescriber or pharmacist if you have any questions about vitamin supplements.
• DO NOT SHARE SORIATANE with anyone else, even if they have the
same symptoms. Your medicine may harm them or their unborn child.
What are the possible side effects of SORIATANE?
SORIATANE can cause serious side effects. See “What is the most important
information I should know about SORIATANE?” and “What are the
important warnings and instructions for females taking SORIATANE?”
Stop taking SORIATANE and call your prescriber right away if you get the
following signs or symptoms of possible serious side effects:
• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be
signs of increased brain pressure that can lead to blindness or even death.
• Decreased vision in the dark (night blindness). Since this can start suddenly,
you should be very careful when driving at night. This problem usually goes
away when SORIATANE treatment stops. If you develop any vision problems or
eye pain stop taking SORIATANE and call your prescriber.
• Depression. There have been some reports of patients developing mental
problems including a depressed mood, aggressive feelings, or thoughts of
ending their own life (suicide). These events, including suicidal behavior, have
been reported in patients taking other drugs similar to SORIATANE as well as
patients taking SORIATANE. Since other things may have contributed to these
problems, it is not known if they are related to SORIATANE.
• Aches or pains in your bones, joints, muscles, or back; trouble moving;
loss of feeling in your hands or feet. These can be signs of abnormal
changes to your bones or muscles.
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• Frequent urination, great thirst or hunger. SORIATANE can affect blood
sugar control, even if you do not already have diabetes. These are some of the
signs of high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble
speaking, or swelling of a leg. These may be signs of a heart attack,
blood clots, or stroke. SORIATANE can cause serious changes in blood fats
(lipids). It is possible for these changes to cause blood vessel blockages that
lead to heart attacks, strokes, or blood clots.
Common side effects
If you develop any of these side effects or any unusual reaction, check with your
prescriber to find out if you need to change the amount of SORIATANE you take.
These side effects usually get better if the dose of SORIATANE is reduced or
SORIATANE is stopped.
• Chapped lips; peeling fingertips, palms, and soles; itching; scaly skin all
over; weak nails; sticky or fragile (weak) skin; runny or dry nose, or
nosebleeds. Your prescriber or pharmacist can recommend a lotion or cream to
help treat drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
• Hair loss. Most patients have some hair loss, but this condition varies among
patients. No one can tell if you will lose hair, how much hair you may lose or if
and when it may grow back.
• Dry eyes. SORIATANE may dry your eyes. Wearing contact lenses may be
uncomfortable during and after treatment with SORIATANE because of the dry
feeling in your eyes. If this happens, remove your contact lenses and call your
prescriber. Also read the section about vision under “Serious side effects”.
• Rise in blood fats (lipids). SORIATANE can cause your blood fats (lipids) to
rise. Most of the time this is not serious. But sometimes the increase can
become a serious problem (see information under “Serious side effects”). You
should have blood tests as directed by your prescriber.
Psoriasis gets worse for some patients when they first start treatment with
SORIATANE. Some patients have more redness or itching. If this happens, tell your
prescriber. These symptoms usually get better as treatment continues, but your
prescriber may need to change the amount of your medicine.
These are not all the possible side effects of SORIATANE. For more information, ask
your prescriber or pharmacist.
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Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store SORIATANE?
Keep SORIATANE away from sunlight, high temperature, and humidity.
Keep SORIATANE and all medicines out of the reach of children.
What are the ingredients in SORIATANE?
Active ingredient: acitretin
Inactive ingredients: black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate. Gelatin capsule
shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide.
They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate
calcium disodium.
General information about the safe and effective use of SORIATANE
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use SORIATANE for a condition for which it was not
prescribed. Do not give SORIATANE to other people, even if they have the same
symptoms that you have.
This Medication Guide summarizes the most important information about
SORIATANE. If you would like more information, talk with your prescriber. You can
ask your pharmacist or prescriber for information about SORIATANE that is written
for health professionals.
For more information about SORIATANE call 1-888-784-3335 or go to
www.soriatane.com.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Manufactured for company logo
Stiefel Laboratories, Inc.
Research Triangle Park, NC 27709
Revised 02/2014
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TEGISON® is a registered trademark of Hoffmann-La Roche Inc.
Do Your P.A.R.T. is a trademark and SORIATANE is a registered trademark of
Stiefel Laboratories, Inc.
©2014, Stiefel Laboratories, Inc
SRN:xMG
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custom-source
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019821s022lbl.pdf', 'application_number': 19821, 'submission_type': 'SUPPL ', 'submission_number': 22}
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NDA 019821/S-024
Page 3
SORIATANE®
(acitretin)
Capsules Do Not get pregnant
CONTRAINDICTIONS AND WARNINGS: Pregnancy
SORIATANE must not be used by females who are pregnant, or who intend to become
pregnant during therapy or at any time for at least 3 years following discontinuation of
therapy. SORIATANE also must not be used by females who may not use reliable
contraception while undergoing treatment and for at least 3 years following
discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON®), and
major human fetal abnormalities have been reported with the administration of acitretin
and etretinate. Potentially, any fetus exposed can be affected.
Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been
associated with the formation of etretinate, which has a significantly longer elimination
half-life than acitretin. Because the longer elimination half-life of etretinate would increase
the duration of teratogenic potential for female patients, ethanol must not be ingested by
female patients either during treatment with SORIATANE or for 2 months after cessation
of therapy. This allows for elimination of acitretin, thus removing the substrate for
transesterification to etretinate. The mechanism of the metabolic process for conversion of
acitretin to etretinate has not been fully defined. It is not known whether substances other
than ethanol are associated with transesterification.
Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats
at oral doses of 0.6, 3, and 15 mg/kg, respectively. These doses are approximately 0.2, 0.3,
and 3 times the maximum recommended therapeutic dose, respectively, based on a mg/m2
comparison.
Major human fetal abnormalities associated with acitretin and/or etretinate
administration have been reported including meningomyelocele; meningoencephalocele;
multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges;
malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial
volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae.
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SORIATANE should be prescribed only by those who have special competence in the
diagnosis and treatment of severe psoriasis, are experienced in the use of systemic
retinoids, and understand the risk of teratogenicity.
Because of the teratogenicity of SORIATANE, a program called the Do Your P.A.R.T
program, Pregnancy Prevention Actively Required During and After Treatment, has been
developed to educate women of childbearing potential and their healthcare providers about
the serious risks associated with acitretin and to help prevent pregnancies from occurring
with the use of this drug and for 3 years after its discontinuation. The Do Your P.A.R.T.
program requirements are described below and program materials are available at
www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784
3335 (1-888-STIEFEL) (see also PRECAUTIONS section).
Important Information for Women of Childbearing Potential:
SORIATANE should be considered only for women with severe psoriasis unresponsive
to other therapies or whose clinical condition contraindicates the use of other treatments.
Females of reproductive potential must not be given a prescription for SORIATANE
until pregnancy is excluded. SORIATANE is contraindicated in females of reproductive
potential unless the patient meets ALL of the following conditions:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at
least 25 mIU/mL before receiving the initial prescription for SORIATANE. The first
test (a screening test) is obtained by the prescriber when the decision is made to
pursue therapy with SORIATANE. The second pregnancy test (a confirmation test)
should be done during the first 5 days of the menstrual period immediately
preceding the beginning of therapy with SORIATANE. For patients with
amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception
[birth control] simultaneously).
• Must have a pregnancy test repeated every month during treatment with
SORIATANE. The patient must have a negative result from a urine or serum
pregnancy test before receiving a prescription for SORIATANE. To encourage
compliance with this recommendation, a limited supply of the drug should be
prescribed. For at least 3 years after discontinuing therapy with SORIATANE, a
pregnancy test must be repeated every 3 months.
• Must have selected and have committed to use 2 effective forms of contraception
(birth control) simultaneously, at least 1 of which must be a primary form, unless
absolute abstinence is the chosen method, or the patient has undergone a
hysterectomy or is clearly postmenopausal.
• Patients must use 2 effective forms of contraception (birth control) simultaneously
for at least 1 month prior to initiation of therapy with SORIATANE, during
therapy with SORIATANE, and for at least 3 years after discontinuing therapy with
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SORIATANE. A SORIATANE Referral Form is available so that patients can
receive an initial free contraceptive counseling session and pregnancy testing.
Counseling about contraception and behaviors associated with an increased risk of
pregnancy must be repeated on a monthly basis by the prescriber during therapy
with SORIATANE and every 3 months for at least 3 years following discontinuation
of SORIATANE.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products.
Secondary forms of contraception include latex condoms (with or without
spermicide), diaphragms and cervical caps (which must be used with a spermicide).
Any birth control method can fail. Therefore, it is critically important that women
of childbearing potential use 2 effective forms of contraception (birth control)
simultaneously. It has not been established if there is a pharmacokinetic interaction
between acitretin and combined oral contraceptives. However, it has been
established that acitretin interferes with the contraceptive effect of microdosed
progestin preparations.1 Microdosed “minipill” progestin preparations are not
recommended for use with SORIATANE. It is not known whether other
progestational contraceptives, such as implants and injectables, are adequate methods
of contraception during acitretin therapy. Prescribers are advised to consult the
package insert of any medication administered concomitantly with hormonal
contraceptives, since some medications may decrease the effectiveness of these birth
control products. Patients should be prospectively cautioned not to self-medicate
with the herbal supplement St. John’s wort because a possible interaction has been
suggested with hormonal contraceptives based on reports of breakthrough bleeding
on oral contraceptives shortly after starting St. John’s wort. Pregnancies have been
reported by users of combined hormonal contraceptives who also used some form of
St. John’s wort (see PRECAUTIONS).
• Must have signed a Patient Agreement/Informed Consent for Female Patients that
contains warnings about the risk of potential birth defects if the fetus is exposed to
SORIATANE, about contraceptive failure, about the fact that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2
months after SORIATANE treatment has been discontinued, and about preventing
pregnancy while taking SORIATANE and for at least 3 years after discontinuing
SORIATANE.
If pregnancy does occur during therapy with SORIATANE or at any time for at
least 3 years following discontinuation of SORIATANE, the prescriber and patient
should discuss the possible effects on the pregnancy. The available information is as
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follows:
Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated
during pregnancy. The risk of severe fetal malformations is well established when
systemic retinoids are taken during pregnancy. Pregnancy must also be prevented
after stopping acitretin therapy, while the drug is being eliminated to below a
threshold blood concentration that would be associated with an increased incidence
of birth defects. Because this threshold has not been established for acitretin in
humans and because elimination rates vary among patients, the duration of
posttherapy contraception to achieve adequate elimination cannot be calculated
precisely. It is strongly recommended that contraception be continued for at least 3
years after stopping treatment with acitretin, based on the following considerations:
o In the absence of transesterification to form etretinate, greater than 98% of
the acitretin would be eliminated within 2 months, assuming a mean
elimination half-life of 49 hours.
o In cases where etretinate is formed, as has been demonstrated with
concomitant administration of acitretin and ethanol,
greater than 98% of the etretinate formed would be eliminated in 2 years,
assuming a mean elimination half-life of 120 days.
greater than 98% of the etretinate formed would be eliminated in 3 years, based
on the longest demonstrated elimination half-life of 168 days.
However, etretinate was found in plasma and subcutaneous fat in one patient
reported to have had sporadic alcohol intake, 52 months after she stopped
acitretin therapy.2
• Severe birth defects have been reported where conception occurred during the time
interval when the patient was being treated with acitretin and/or etretinate. In
addition, severe birth defects have also been reported when conception occurred
after the mother completed therapy. These cases have been reported both
prospectively (before the outcome was known) and retrospectively (after the
outcome was known). The events below are listed without distinction as to whether
the reported birth defects are consistent with retinoid-induced embryopathy or not.
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There have been 318 prospectively reported cases involving pregnancies and the
use of etretinate, acitretin, or both. In 238 of these cases, the conception
occurred after the last dose of etretinate (103 cases), acitretin (126), or both (9).
Fetal outcome remained unknown in approximately one-half of these cases, of
which 62 were terminated and 14 were spontaneous abortions. Fetal outcome is
known for the other 118 cases and 15 of the outcomes were abnormal (including
cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia,
limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental
disorder/death, undescended testicle, and 5 cases of premature birth). In the 126
prospectively reported cases where conception occurred after the last dose of
acitretin only, 43 cases involved conception at least 1 year but less than 2 years
after the last dose. There were 3 reports of abnormal outcomes out of these 43
cases (involving limb malformation, GI tract malformations, and premature
birth). There were only 4 cases where conception occurred at least 2 years after
the last dose but there were no reports of birth defects in these cases.
There is also a total of 35 retrospectively reported cases where conception
occurred at least 1 year after the last dose of etretinate, acitretin, or both. From
these cases there are 3 reports of birth defects when the conception occurred at
least 1 year but less than 2 years after the last dose of acitretin (including heart
malformations, Turner’s Syndrome, and unspecified congenital malformations)
and 4 reports of birth defects when conception occurred 2 or more years after
the last dose of acitretin (including foot malformation, cardiac malformations [2
cases], and unspecified neonatal and infancy disorder). There were 3 additional
abnormal outcomes in cases where conception occurred 2 or more years after
the last dose of etretinate (including chromosome disorder, forearm aplasia, and
stillbirth).
Females who have taken TEGISON (etretinate) must continue to follow the
contraceptive recommendations for TEGISON. TEGISON is no longer
marketed in the US; for information, call Stiefel at 1-888-784-3335 (1-888
STIEFEL).
Patients should not donate blood during and for at least 3 years following the
completion of therapy with SORIATANE because women of childbearing
potential must not receive blood from patients being treated with SORIATANE.
Important Information For Males Taking SORIATANE:
Patients should not donate blood during and for at least 3 years following therapy
with SORIATANE because women of childbearing potential must not receive blood
from patients being treated with SORIATANE.
• Samples of seminal fluid from 3 male patients treated with acitretin and 6 male
patients treated with etretinate have been assayed for the presence of acitretin. The
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maximum concentration of acitretin observed in the seminal fluid of these men was
12.5 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug
transferred in semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule.
Thus, although it appears that residual acitretin in seminal fluid poses little, if any,
risk to a fetus while a male patient is taking the drug or after it is discontinued, the
no-effect limit for teratogenicity is unknown and there is no registry for birth
defects associated with acitretin. The available data are as follows:
There have been 25 cases of reported conception when the male partner was taking
acitretin. The pregnancy outcome is known in 13 of these 25 cases. Of these, 9 reports
were retrospective and 4 were prospective (meaning the pregnancy was reported prior to
knowledge of the outcome)3 .
Timing of Paternal
Acitretin Treatment
Relative to Conception
Delivery of
Healthy
Neonate
Spontaneous
Abortion
Induced
Abortion
Total
At time of conception
5a
5
1
11
Discontinued ~4 weeks prior
0
0
1b
1
Discontinued ~6 to 8 months prior
0
1
0
1
a Four of 5 cases were prospective.
b With malformation pattern not typical of retinoid embryopathy (bilateral cystic hygromas of
neck, hypoplasia of lungs bilateral, pulmonary atresia, VSD with overriding truncus arteriosus).
For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE
PATIENT EACH TIME SORIATANE IS DISPENSED, AS REQUIRED BY LAW.
DESCRIPTION
SORIATANE (acitretin), a retinoid, is available in 10 mg, 17.5 mg, and 25 mg gelatin
capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6
trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is
related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder
with a molecular weight of 326.44. The structural formula is: structural formula
Each capsule contains acitretin, black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate.
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Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium
dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium
disodium.
CLINICAL PHARMACOLOGY
The mechanism of action of SORIATANE is unknown.
Pharmacokinetics: Absorption: Oral absorption of acitretin is optimal when given with
food. For this reason, acitretin was given with food in all of the following trials. After
administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma
concentrations ranged from 196 to 728 ng/mL (mean: 416 ng/mL) and were achieved in 2 to 5
hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with
increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the
administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy
subjects.
Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism: (See Pharmacokinetic Drug Interactions: Ethanol.) Following oral
absorption, acitretin undergoes extensive metabolism and interconversion by simple
isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent
compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both
parent compound and isomer are further metabolized into chain-shortened breakdown products
and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-
state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3
weeks.
Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin
are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal
elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to
96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157
hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
Special Populations: Psoriasis: In an 8-week trial of acitretin pharmacokinetics in
subjects with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose-
proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma
concentrations were nonmeasurable (<4 ng/mL) in all subjects 3 weeks after cessation of
therapy.
Elderly: In a multiple-dose trial in healthy young (n = 6) and elderly (n = 8) subjects, a
2-fold increase in acitretin plasma concentrations were seen in elderly subjects, although the
elimination half-life did not change.
Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in
subjects with end-stage renal failure (n = 6) when compared with age-matched controls,
following single 50 mg oral doses. Acitretin was not removed by hemodialysis in these subjects.
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Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND
WARNINGS and PRECAUTIONS: Drug Interactions): In studies of in vivo
pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine,
digoxin, phenprocoumon, or glyburide.
Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-
life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way
crossover trial, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg oral
dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately
1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range: 22 to 105
ng/mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate
in this trial was comparable to a single 5 mg oral dose of etretinate. There was no detectable
formation of etretinate when a single 100 mg oral dose of acitretin was administered without
concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol
ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93
evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to 80 mg/day), 16%
had measurable etretinate levels (>5 ng/mL).
Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial
the apparent mean terminal half-life after 6 months of therapy was approximately 120 days
(range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had
detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was
discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.
Progestin-only Contraceptives: It has not been established if there is a
pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has
been established that acitretin interferes with the contraceptive effect of microdosed progestin
preparations.1 Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE. It is not known whether other progestational contraceptives, such as implants and
injectables, are adequate methods of contraception during acitretin therapy.
CLINICAL STUDIES
In 2 double-blind, placebo-controlled trials, SORIATANE was administered once daily to
subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8
weeks (see Table 1) subjects treated in Trial A with 50 mg of SORIATANE per day showed
significant improvements (P ≤0.05) relative to baseline and to placebo in the physician’s global
evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In
Trial B, differences from baseline and from placebo were statistically significant (P ≤0.05) for all
variables at both the 25 mg and 50 mg doses; it should be noted for Trial B that no statistical
adjustment for multiplicity was carried out.
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Table 1. Summary of the Efficacy Results of the 8-Week Double-Blind Phase of Trials A
and B of SORIATANE
Efficacy Variables
Trial A
Trial B
Total Daily Dose
Total Daily Dose
Placebo
(N = 29)
50 mg
(N = 29)
Placebo
(N = 72)
25 mg
(N = 74)
50 mg
(N = 71)
Physician’s
Global Evaluation
Baseline
Mean Change
After 8 Weeks
4.62
−0.29
4.55
−2.00a
4.43
−0.06
4.37
−1.06a
4.49
−1.57a
Scaling
Baseline
Mean Change
After 8 Weeks
4.10
−0.22
3.76
−1.62a
3.97
−0.21
4.11
−1.50a
4.10
−1.78a
Thickness
Baseline
Mean Change
After 8 Weeks
4.10
−0.39
4.10
−2.10 a
4.03
−0.18
4.11
−1.43 a
4.20
−2.11 a
Erythema
Baseline
Mean Change
After 8 Weeks
4.21
−0.33
4.59
−2.10a
4.42
−0.37
4.24
−1.12a
4.45
−1.65a
a Values were statistically significantly different from placebo and from baseline (P ≤0.05). No
adjustment for multiplicity was done for Trial B.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
A subset of 141 subjects from both pivotal Trials A and B continued to receive SORIATANE
in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables,
as indicated in Table 2, were significantly improved (P ≤0.01) from baseline, including extent of
psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.
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Table 2. Summary of the First Course of Therapy With SORIATANE (24 Weeks)
Variables
Trial A
Trial B
Mean Total Daily Dose of SORIATANE (mg)
42.8
43.1
Mean Duration of Therapy (Weeks)
21.1
22.6
Physician’s Global Evaluation
Baseline
Mean Change From Baseline
N = 39
4.51
−2.26a
N = 98
4.43
−2.60a
Scaling
Baseline
Mean Change From Baseline
N = 59
3.97
−2.15a
N = 132
4.07
−2.42a
Thickness
Baseline
Mean Change From Baseline
N = 59
4.00
−2.44 a
N = 132
4.12
−2.66 a
Erythema
Baseline
Mean Change From Baseline
N = 59
4.35
−2.31a
N = 132
4.33
−2.29a
a Indicates that the difference from baseline was statistically significant (P ≤0.01).
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated
for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a
small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course
of therapy (for a total of 18 months of treatment).
INDICATIONS AND USAGE
SORIATANE is indicated for the treatment of severe psoriasis in adults. Because of
significant adverse effects associated with its use, SORIATANE should be prescribed only by
those knowledgeable in the systemic use of retinoids. In females of reproductive potential,
SORIATANE should be reserved for non-pregnant patients who are unresponsive to other
therapies or whose clinical condition contraindicates the use of other treatments (see boxed
CONTRAINDICATIONS AND WARNINGS — SORIATANE can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses,
when clinically indicated, have produced efficacy results similar to the initial course of therapy.
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CONTRAINDICATIONS
Pregnancy Category X: (See boxed CONTRAINDICATIONS AND WARNINGS.)
SORIATANE is contraindicated in patients with severely impaired liver or kidney function
and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS:
Hepatotoxicity, WARNINGS: Lipids and Possible Cardiovascular Effects, and
PRECAUTIONS).
An increased risk of hepatitis has been reported to result from combined use of methotrexate
and etretinate. Consequently, the combination of methotrexate with SORIATANE is also
contraindicated (see PRECAUTIONS: Drug Interactions).
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri).
SORIATANE is contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to
the preparation (acitretin or excipients) or to other retinoids.
WARNINGS
(See also boxed CONTRAINDICATIONS AND WARNINGS.)
Hepatotoxicity: Of the 525 subjects treated in US clinical trials, 2 had clinical jaundice
with elevated serum bilirubin and transaminases considered related to treatment with
SORIATANE. Liver function test results in these subjects returned to normal after
SORIATANE was discontinued. Two of the 1,289 subjects treated in European clinical
trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects
revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial
of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject
showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal
tracts compatible with acute reversible hepatic injury. The subject's transaminase levels
returned to normal 2 months after SORIATANE was discontinued.
The potential of therapy with SORIATANE to induce hepatotoxicity was prospectively
evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and
posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings
before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%)
improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6
subjects, the classification changed from class 0 (no pathology) to class I (normal fatty
infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the
change was from class I to class II (fatty infiltration, nuclear variability, portal
inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was
from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found
between liver function test result abnormalities and the change in liver biopsy status, and
no cumulative dose relationship was found.
Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in
approximately 1 in 3 subjects treated with SORIATANE. Of the 525 subjects treated in
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clinical trials in the US, treatment was discontinued in 20 (3.8%) due to elevated liver
function test results. If hepatotoxicity is suspected during treatment with SORIATANE, the
drug should be discontinued and the etiology further investigated.
Ten of 652 subjects treated in US clinical trials of etretinate, of which acitretin is the
active metabolite, had clinical or histologic hepatitis considered to be possibly or probably
related to etretinate treatment.
There have been reports of hepatitis-related deaths worldwide; a few of these subjects
had received etretinate for a month or less before presenting with hepatic symptoms or
signs.
Hyperostosis: In adults receiving long-term treatment with SORIATANE, appropriate
examinations should be periodically performed in view of possible ossification abnormalities
(see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic bony
abnormality in adults is low, periodic radiography is only warranted in the presence of symptoms
or long-term use of SORIATANE. If such disorders arise, the continuation of therapy should be
discussed with the patient on the basis of a careful risk/benefit analysis. In clinical trials with
SORIATANE, subjects were prospectively evaluated for evidence of development or change in
bony abnormalities of the vertebral column, knees, and ankles.
Vertebral Results: Of 380 subjects treated with SORIATANE, 15% had preexisting
abnormalities of the spine which showed new changes or progression of preexisting findings.
Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic
skeletal hyperostosis, ligament calcification, and narrowing and destruction of a cervical disc
space. De novo changes (formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.
Skeletal Appendicular Results: Six of 128 subjects treated with SORIATANE showed
abnormalities in the knees and ankles before treatment that progressed during treatment. In 5,
these changes involved the formation of additional spurs or enlargement of existing spurs. The
sixth subject had degenerative joint disease which worsened. No subjects developed spurs de
novo. Clinical complaints did not predict radiographic changes.
Lipids and Possible Cardiovascular Effects: Blood lipid determinations should be
performed before SORIATANE is administered and again at intervals of 1 to 2 weeks until the
lipid response to the drug is established, usually within 4 to 8 weeks. In subjects receiving
SORIATANE during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of
subjects. These effects of SORIATANE were generally reversible upon cessation of therapy.
Subjects with an increased tendency to develop hypertriglyceridemia included those with
disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a
familial history of these conditions. Because of the risk of hypertriglyceridemia, serum lipids
must be more closely monitored in high-risk patients and during long-term treatment.
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Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status.
Although no causal relationship has been established, there have been postmarketing reports of
acute myocardial infarction or thromboembolic events in patients on therapy with SORIATANE.
In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated with
fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of SORIATANE,
or drug therapy should be employed to control significant elevations of triglycerides. If, despite
these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of
SORIATANE should be considered.
Ophthalmologic Effects: The eyes and vision of 329 subjects treated with SORIATANE
were examined by ophthalmologists. The findings included dry eyes (23%), irritation of eyes
(9%), and brow and lash loss (5%). The following were reported in less than 5% of patients:
Bell’s Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial
abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear
cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and
subepithelial corneal lesions.
Any patient treated with SORIATANE who is experiencing visual difficulties should
discontinue the drug and undergo ophthalmologic evaluation.
Pancreatitis: Lipid elevations occur in 25% to 50% of patients treated with SORIATANE.
Triglyceride increases sufficient to be associated with pancreatitis are much less common,
although fatal fulminant pancreatitis has been reported. There have been rare reports of
pancreatitis during therapy with SORIATANE in the absence of hypertriglyceridemia.
Pseudotumor Cerebri: SORIATANE and other retinoids administered orally have been
associated with cases of pseudotumor cerebri (benign intracranial hypertension). Some of these
events involved concomitant use of isotretinoin and tetracyclines. However, the event seen in a
single patient receiving SORIATANE was not associated with tetracycline use. Early signs and
symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Patients
with these signs and symptoms should be examined for papilledema and, if present, should
discontinue SORIATANE immediately and be referred for neurological evaluation and care.
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see CONTRAINDICATIONS).
Capillary Leak Syndrome: Capillary leak syndrome, a potential manifestation of retinoic
acid syndrome, has been reported in patients receiving SORIATANE. Features of this syndrome
may include localized or generalized edema with secondary weight gain, fever, and hypotension.
Rhabdomyolysis and myalgias have been reported in association with capillary leak syndrome,
and laboratory tests may reveal neutrophilia, hypoalbuminemia, and an elevated hematocrit.
Discontinue SORIATANE if capillary leak syndrome develops during therapy.
Exfoliative Dermatitis/Erythroderma: Exfoliative dermatitis/erythroderma has been
reported in patients receiving SORIATANE. Discontinue SORIATANE if exfoliative
dermatitis/erythroderma occurs during therapy.
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PRECAUTIONS
A description of the Do Your P.A.R.T. materials is provided below. The main goals of the
materials are to explain the program requirements, to reinforce the educational messages, and to
assess program effectiveness.
The Do Your P.A.R.T. booklet includes:
• The Do Your P.A.R.T. Patient Brochure: information on the program requirements, risks of
acitretin, and the types of contraceptive methods
• The Contraceptive Counseling Referral Form for female patients who want to receive free
contraception counseling reimbursed by the manufacturer
• The Patient Agreement/Informed Consent Form for female patients
• Medication Guide
The Do Your P.A.R.T. program also includes a voluntary patient survey for women of
childbearing potential to assess the effectiveness of the SORIATANE Pregnancy Prevention
Program Do Your P.A.R.T. Do Your P.A.R.T Program materials are available at
www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784-3335
(1-888-STIEFEL).
Information for Patients:
(See Medication Guide for all patients and Patient Agreement/Informed Consent for
Female Patients at end of professional labeling.)
Patients should be instructed to read the Medication Guide supplied as required by law when
SORIATANE is dispensed.
Females of Reproductive Potential: SORIATANE can cause severe birth defects.
Female patients must not be pregnant when therapy with SORIATANE is initiated, they must not
become pregnant while taking SORIATANE and for at least 3 years after stopping
SORIATANE, so that the drug can be eliminated to below a blood concentration that would be
associated with an increased incidence of birth defects. Because this threshold has not been
established for acitretin in humans and because elimination rates vary among patients, the
duration of posttherapy contraception to achieve adequate elimination cannot be calculated
precisely (see boxed CONTRAINDICATIONS AND WARNINGS).
Females of reproductive potential should also be advised that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2 months
after SORIATANE has been discontinued. This allows for elimination of the acitretin which
can be converted to etretinate in the presence of alcohol.
Female patients should be advised that any method of birth control can fail, including tubal
ligation, and that microdosed progestin “minipill” preparations are not recommended for use
with SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions).
Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel
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0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during
acitretin treatment.2
Female patients should sign a consent form prior to beginning therapy with SORIATANE (see
boxed CONTRAINDICATIONS AND WARNINGS).
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the
milk. There is one prospective case report where acitretin is reported to be excreted in human
milk. Therefore, nursing mothers should not receive SORIATANE prior to or during nursing
because of the potential for serious adverse reactions in nursing infants.
All Patients: Depression and/or other psychiatric symptoms such as aggressive feelings
or thoughts of self-harm have been reported. These events, including self-injurious behavior,
have been reported in patients taking other systemically administered retinoids, as well as in
patients taking SORIATANE. Since other factors may have contributed to these events, it is not
known if they are related to SORIATANE. Patients should be counseled to stop taking
SORIATANE and notify their prescriber immediately if they experience psychiatric symptoms.
Patients should be advised that a transient worsening of psoriasis is sometimes seen during the
initial treatment period. Patients should be advised that they may have to wait 2 to 3 months
before they get the full benefit of SORIATANE, although some patients may achieve significant
improvements within the first 8 weeks of treatment as demonstrated in clinical trials.
Decreased night vision has been reported during therapy with SORIATANE. Patients should
be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night. Visual problems should be carefully monitored (see WARNINGS and
ADVERSE REACTIONS). Patients should be advised that they may experience decreased
tolerance to contact lenses during the treatment period and sometimes after treatment has
stopped.
Patients should not donate blood during and for at least 3 years following therapy because
SORIATANE can cause birth defects and women of childbearing potential must not receive
blood from patients being treated with SORIATANE.
Because of the relationship of SORIATANE to vitamin A, patients should be advised against
taking vitamin A supplements in excess of minimum recommended daily allowances to avoid
possible additive toxic effects.
Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical
UV exposure) because the effects of UV light are enhanced by retinoids.
Patients should be advised that they must not give their SORIATANE to any other person.
For Prescribers: SORIATANE has not been studied in and is not indicated for treatment of
acne.
Phototherapy: Significantly lower doses of phototherapy are required when
SORIATANE is used because effects on the stratum corneum induced by SORIATANE can
increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).
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Drug Interactions: Ethanol: Clinical evidence has shown that etretinate can be formed with
concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND
WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Glyburide: In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood
glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7
subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not
detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under
treatment with SORIATANE is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Hormonal Contraceptives: It has not been established if there is a pharmacokinetic
interaction between acitretin and combined oral contraceptives. However, it has been established
that acitretin interferes with the contraceptive effect of microdosed progestin “minipill”
preparations. Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). It is
not known whether other progestational contraceptives, such as implants and injectables, are
adequate methods of contraception during acitretin therapy.
Methotrexate: An increased risk of hepatitis has been reported to result from combined use
of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is
also contraindicated (see CONTRAINDICATIONS).
Phenytoin: If acitretin is given concurrently with phenytoin, the protein binding of
phenytoin may be reduced.
Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial
pressure, their combined use is contraindicated (see CONTRAINDICATIONS and
WARNINGS: Pseudotumor Cerebri).
Vitamin A and Oral Retinoids: Concomitant administration of vitamin A and/or other oral
retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.
Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine,
digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of
anticoagulants of the coumarin type (warfarin) revealed no interaction.
Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage
reduction with careful monitoring or treatment discontinuation is recommended, depending on
clinical judgment.
Blood Sugar: Some patients receiving retinoids have experienced problems with blood
sugar control. In addition, new cases of diabetes have been diagnosed during retinoid therapy,
including diabetic ketoacidosis. In diabetics, blood-sugar levels should be monitored very
carefully.
Lipids: In clinical trials, the incidence of hypertriglyceridemia was 66%,
hypercholesterolemia was 33%, and that of decreased HDL was 40%. Pretreatment and follow-
up measurements should be obtained under fasting conditions. It is recommended that these tests
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be performed weekly or every other week until the lipid response to SORIATANE has stabilized
(see WARNINGS).
Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT), or LDH were
experienced by approximately 1 in 3 patients treated with SORIATANE. It is recommended that
these tests be performed prior to initiation of therapy with SORIATANE, at 1- to 2-week
intervals until stable, and thereafter at intervals as clinically indicated (see
CONTRAINDICATIONS and boxed WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A
carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg/kg/day administered 7
days/week for 104 weeks, has been completed. There were no neoplastic lesions observed that
were considered to have been related to treatment with acitretin. An 80-week carcinogenesis
study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data
obtained during this study demonstrated that etretinate was metabolized to acitretin and that
blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study,
an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several
different sites) was noted in male, but not female, mice at doses approximately one-half the
maximum recommended human therapeutic dose based on a mg/m2 comparison.
Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the
Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat
hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of
mutagenicity of acitretin was demonstrated in any of these assays.
Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not
impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the
maximum recommended therapeutic dose based on a mg/m2 comparison). Chronic toxicity
studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and
appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day).
No decreases in sperm count or concentration and no changes in sperm motility or
morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of
keratinization, and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks.
In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in
any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any
of the 18 men where it was measured.4,5
Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed
CONTRAINDICATIONS AND WARNINGS).
In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for
10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with
untreated female rats, no teratogenic effects were observed in the progeny (see boxed
CONTRAINDICATIONS AND WARNINGS for information about male use of SORIATANE).
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Nonteratogenic Effects: In rats dosed at 3 mg/kg/day (approximately one-half the
maximum recommended therapeutic dose based on a mg/m2 comparison), slightly decreased pup
survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg/kg/day, no
treatment-related adverse effects were observed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No
clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments
and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and
premature epiphyseal closure have been reported in children taking other systemic retinoids,
including etretinate, a metabolite of SORIATANE. A causal relationship between these effects
and SORIATANE has not been established. While it is not known that these occurrences are
more severe or more frequent in children, there is special concern in pediatric patients because of
the implications for growth potential (see WARNINGS: Hyperostosis).
Geriatric Use: Clinical trials of SORIATANE did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently than younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger subjects. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in
acitretin plasma concentrations was seen in healthy elderly subjects compared with young
subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY:
Special Populations).
ADVERSE REACTIONS
Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the
mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many
of the clinical adverse reactions reported to date with administration of SORIATANE resemble
those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports: In addition to the events listed in the tables for
the clinical trials, the following adverse events have been identified during postapproval use of
SORIATANE. Because these events are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism (see WARNINGS),
stroke.
Immune System Disorders: Hypersensitivity, including angioedema and urticaria (see
CONTRAINDICATIONS).
Nervous System: Myopathy with peripheral neuropathy has been reported during therapy
with SORIATANE. Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events,
including self-injurious behavior, have been reported in patients taking other systemically
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administered retinoids, as well as in patients taking SORIATANE. Since other factors may have
contributed to these events, it is not known if they are related to SORIATANE (see
PRECAUTIONS).
Reproductive: Vulvo-vaginitis due to Candida albicans.
Skin and Appendages: Thinning of the skin, skin fragility, and scaling may occur all over
the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and
exfoliative dermatitis/erythroderma have been reported (see WARNINGS).
Vascular Disorders: Capillary leak syndrome (see WARNINGS).
Clinical Trials: During clinical trials with SORIATANE, 513/525 (98%) of subjects reported a
total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely,
primarily because of adverse experiences involving the mucous membranes and skin. Three
subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung
cancer); the other subject died of an acute myocardial infarction, considered remotely related to
drug therapy. In clinical trials, SORIATANE was associated with elevations in liver function test
results or triglyceride levels and hepatitis.
The tables below list by body system and frequency the adverse events reported during
clinical trials of 525 subjects with psoriasis.
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Table 3. Adverse Events Frequently Reported During Clinical Trials
Percent of Subjects Reporting (N = 525)
Body System
>75%
50% to 75%
25% to 50%
10% to 25%
CNS
Rigors
Eye Disorders
Xerophthalmia
Mucous Membranes
Cheilitis
Rhinitis
Dry mouth
Epistaxis
Musculoskeletal
Arthralgia
Spinal hyperostosis
(progression of
existing lesions)
Skin and Appendages
Alopecia
Skin peeling
Dry skin
Nail disorder
Pruritus
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Table 4. Adverse Events Less Frequently Reported During Clinical Trials (Some of Which
May Bear No Relationship to Therapy)
Percent of Subjects Reporting (N = 525)
Body System
1% to 10%
<1%
Body as a Whole
Anorexia
Edema
Fatigue
Hot flashes
Increased appetite
Alcohol
intolerance
Dizziness
Fever
Influenza-like
symptoms
Malaise
Moniliasis
Muscle weakness
Weight increase
Cardiovascular
Flushing
Chest pain
Cyanosis
Increased
bleeding time
Intermittent
claudication
Peripheral
ischemia
CNS (also see
Psychiatric)
Headache
Pain
Abnormal gait
Migraine
Neuritis
Pseudotumor
cerebri
(intracranial
hypertension)
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Eye Disorders
Abnormal/
blurred vision
Blepharitis
Conjunctivitis/
irritation
Corneal epithelial
abnormality
Decreased night
vision/night
blindness
Eye abnormality
Eye pain
Photophobia
Abnormal
lacrimation
Chalazion
Conjunctival
hemorrhage
Corneal ulceration
Diplopia
Ectropion
Itchy eyes and lids
Papilledema
Recurrent sties
Subepithelial
corneal lesions
Gastrointestinal
Abdominal pain
Diarrhea
Nausea
Tongue disorder
Constipation
Dyspepsia
Esophagitis
Gastritis
Gastroenteritis
Glossitis
Hemorrhoids
Melena
Tenesmus
Tongue ulceration
Liver and Biliary
Hepatic function
abnormal
Hepatitis
Jaundice
Mucous Membranes Gingival bleeding
Gingivitis
Increased saliva
Stomatitis
Thirst
Ulcerative
stomatitis
Altered saliva
Anal disorder
Gum hyperplasia
Hemorrhage
Pharyngitis
Musculoskeletal
Arthritis
Arthrosis
Back pain
Hypertonia
Myalgia
Osteodynia
Peripheral joint
hyperostosis
(progression of
existing lesions)
Bone disorder
Olecranon bursitis
Spinal hyperostosis
(new lesions)
Tendonitis
Psychiatric
Depression
Insomnia
Somnolence
Anxiety
Dysphonia
Libido decreased
Nervousness
Reproductive
Atrophic vaginitis
Leukorrhea
Respiratory
Sinusitis
Coughing
Increased sputum
Laryngitis
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Skin and
Appendages
Abnormal skin
odor
Abnormal hair
texture
Bullous eruption
Cold/clammy skin
Dermatitis
Increased
sweating
Infection
Psoriasiform rash
Purpura
Pyogenic
granuloma
Rash
Seborrhea
Skin fissures
Skin ulceration
Sunburn
Acne
Breast pain
Cyst
Eczema
Fungal infection
Furunculosis
Hair discoloration
Herpes simplex
Hyperkeratosis
Hypertrichosis
Hypoesthesia
Impaired healing
Otitis media
Otitis externa
Photosensitivity
reaction
Psoriasis
aggravated
Scleroderma
Skin nodule
Skin hypertrophy
Skin disorder
Skin irritation
Sweat gland
disorder
Urticaria
Verrucae
Special Senses/
Other
Earache
Taste perversion
Tinnitus
Ceruminosis
Deafness
Taste loss
Urinary
Abnormal urine
Dysuria
Penis disorder
Laboratory: Therapy with SORIATANE induces changes in liver function tests in a
significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were
experienced by approximately 1 in 3 subjects treated with SORIATANE. In most subjects,
elevations were slight to moderate and returned to normal either during continuation of therapy
or after cessation of treatment. In subjects receiving SORIATANE during clinical trials, 66% and
33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density
lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient, usually reversible elevations
of alkaline phosphatase have been observed.
Table 5 lists the laboratory abnormalities reported during clinical trials.
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Table 5. Abnormal Laboratory Test Results Reported During Clinical Trials
Percent of Subjects Reporting
Body System
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Electrolytes
Increased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Magnesium
Decreased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Calcium
–Chloride
Hematologic
Increased:
–Reticulocytes
Decreased:
–Hematocrit
–Hemoglobin
–WBC
Increased:
–Haptoglobin
–Neutrophils
–WBC
Increased:
–Bands
–Basophils
–Eosinophils
–Hematocrit
–Hemoglobin
–Lymphocytes
–Monocytes
Decreased:
–Haptoglobin
–Lymphocytes
–Neutrophils
–Reticulocytes
Increased or
decreased:
–Platelets
–RBC
Hepatic
Increased:
–Cholesterol
–LDH
–SGOT
–SGPT
Decreased:
–HDL cholesterol
Increased:
–Alkaline
phosphatase
–Direct bilirubin
–GGTP
Increased:
–Globulin
–Total bilirubin
–Total protein
Increased and
decreased:
–Serum albumin
Miscellaneous
Increased:
–Triglycerides
Increased:
–CPK
–Fasting blood
sugar
Decreased:
–Fasting blood
sugar
–High occult
blood
Increased and
decreased:
–Iron
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Renal
Increased:
–Uric acid
Increased:
–BUN
–Creatinine
Urinary
WBC in urine
Acetonuria
Hematuria
RBC in urine
Glycosuria
Proteinuria
OVERDOSAGE
In the event of acute overdosage, SORIATANE must be withdrawn at once. Symptoms of
overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral
toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg/kg.
In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25 mg
capsules (525 mg single dose). He vomited several hours later but experienced no other ill
effects.
All female patients of childbearing potential who have taken an overdose of SORIATANE
must:
1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed
CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth
defects and contraceptive use for at least 3 years’ duration after the overdose.
DOSAGE AND ADMINISTRATION
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side
effects with SORIATANE. A number of the more common side effects are dose-related.
Individualization of dosage is required to achieve sufficient therapeutic response while
minimizing side effects. Therapy with SORIATANE should be initiated at 25 to 50 mg per day,
given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be
given dependent upon an individual patient’s response to initial treatment. Relapses may be
treated as outlined for initial therapy.
When SORIATANE is used with phototherapy, the prescriber should decrease the
phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS:
General).
Females who have taken TEGISON (etretinate) must continue to follow the
contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the
US; for information, call Stiefel at 1-888-784-3335 (1-888-STIEFEL).
Information for Pharmacists: A SORIATANE Medication Guide must be given to the
patient each time SORIATANE is dispensed, as required by law.
HOW SUPPLIED:
Brown and white capsules, 10 mg, imprinted “A-10 mg”; bottles of 30 (NDC 0145-0090-25).
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Rich yellow capsules, 17.5 mg, imprinted “A-17.5 mg”; bottles of 30 (NDC 0145-3817-03).
Brown and yellow capsules, 25 mg, imprinted “A-25 mg”; bottles of 30 (NDC 0145-0091
25).
Store between 15° and 25°C (59° and 77°F). Protect from light. Avoid exposure to high
temperatures and humidity after the bottle is opened.
REFERENCES:
1. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389.
2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after
long-term acitretin. Lancet 348:1107, 1996.
3. Geiger JM, Walker M: Is there a reproductive safety risk in male patients treated with acitretin
(Neotigason®/ Soriatane ®)? Dermatology 205:105-107, 2002.
4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica
175:48-49, 1987.
5. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670).
Andrologia 22:479-482, 1990.
6. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin. In:
Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3, pp
253-254, 1988.
PATIENT AGREEMENT/INFORMED CONSENT FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber Do Not get pregnant
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each item.
Do not sign this consent and do not take SORIATANE® (acitretin) if there is anything that
you do not understand.
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects
if I am pregnant or become pregnant while taking SORIATANE in any amount even for short
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periods of time. Birth defects have also happened in babies of women who became pregnant after
stopping treatment with SORIATANE.
INITIAL: ___________
2. I understand that I must not become pregnant while taking SORIATANE and for at least 3
years after the end of my treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter
products that contain alcohol. I understand that the risk of birth defects may last longer than 3
years if I swallow any form of alcohol during therapy with SORIATANE, and for 2 months after
I stop taking SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective forms
of birth control at the same time. The only exceptions are if I have had surgery to remove the
womb (a hysterectomy) or my prescriber has told me I have gone completely through
menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at the same
time for at least one month before starting SORIATANE, for the entire time of therapy with
SORIATANE, and for at least 3 years after stopping SORIATANE.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different methods
at the same time, every time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary:
Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills,
injectable/implantable/insertable/topical (patch) hormonal birth control products, and
IUDs (intrauterine devices). Secondary: Latex condoms (with or without spermicide,
which is a special cream or jelly that kills sperm), diaphragms and cervical caps (which
must be used with a spermicide). I understand that at least 1 of my 2 methods of birth
control must be a primary method.
INITIAL: ___________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to take while
taking SORIATANE because certain birth control methods may not work if I am taking certain
medicines or herbal products (for example, St. John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely through
menopause, I understand that I must have 2 negative pregnancy test results before I can get a
prescription to start SORIATANE. I will then have pregnancy tests on a monthly basis during
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therapy with SORIATANE as instructed by my prescriber. In addition, for at least 3 years after I
stop taking SORIATANE, I will have a pregnancy test every 3 months.
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not
pregnant and have negative results from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraceptive (birth control)
counseling session and pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during therapy with SORIATANE and every 3 months
for at least 3 years after stopping SORIATANE that I should receive counseling from my
prescriber about contraception (birth control) and behaviors associated with an increased risk of
pregnancy.
INITIAL: ___________
14. I understand that I must stop taking SORIATANE right away and call my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without
using my 2 birth control methods during and at least 3 years after stopping SORIATANE.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of stopping
SORIATANE, I understand that I should report my pregnancy to Stiefel at 1-888-784-3335 (1
888-STIEFEL) or to the Food and Drug Administration (FDA) MedWatch program at 1-800
FDA-1088. The information I share will be kept confidential (private) and will help the company
and the FDA evaluate the pregnancy prevention program to prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T™ brochure. My prescriber has answered all
my questions about SORIATANE. I understand that it is my responsibility to follow my
doctor’s instructions, and not to get pregnant during treatment with SORIATANE or for
at least 3 years after I stop taking SORIATANE.
I now authorize my prescriber,
______________________________________________________, to begin my treatment with
SORIATANE.
Patient signature: ________________________________________
Date: ___________________
Parent/guardian signature (if under age 18): ____________________
Date: ___________________
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Please print: Patient name and address:
Telephone: _____________________________________________________________
I have fully explained to the patient,
_________________________________________________, the nature and purpose of the
treatment described above and the risks to females of childbearing potential. I have asked the
patient if she has any questions regarding her treatment with SORIATANE and have answered
those questions to the best of my ability.
Prescriber signature: _______________________________________
Date: __________________
Revised May/2014
SRN:XPI
MEDICATION GUIDE
SORIATANE® (sor-RYE-uh-tane)
(acitretin)
Capsules
Read this Medication Guide carefully before you start taking SORIATANE and read it
each time you get more SORIATANE. There may be new information.
The first information in this Guide is about birth defects and how to avoid
pregnancy. After this section there is important safety information about
possible effects for any patient taking SORIATANE. ALL patients should read
this entire Medication Guide carefully.
This information does not take the place of talking with your prescriber about your
medical condition or treatment.
What is the most important information I should know about SORIATANE?
SORIATANE can cause serious side effects, including:
1. Severe birth defects. If you are a female who can get pregnant, you should
use SORIATANE only if you are not pregnant now, can avoid becoming pregnant for
at least 3 years, and other medicines do not work for your severe psoriasis or you
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cannot use other psoriasis medicines. Information about effects on unborn babies
and about how to avoid pregnancy is found in the next section: “What are the
important warnings and instructions for females taking SORIATANE?” Do Not get pregnant
2. Liver problems, including abnormal liver function tests and inflammation of
your liver (hepatitis). Your prescriber should do blood tests to check how your liver
is working before you start taking and during treatment with SORIATANE. Stop
taking SORIATANE and call your prescriber right away if you have any of the
following signs or symptoms of a serious liver problem:
yellowing of your skin or the whites of your eyes
nausea and vomiting
loss of appetite
dark urine
What are the important warnings and instructions for females taking
SORIATANE?
• Before you receive your first prescription for SORIATANE, you should
have discussed and signed a Patient Information/Consent form with
your prescriber. This is to help make sure you understand the risk of
birth defects and how to avoid getting pregnant. If you did not talk to
your prescriber about this and sign the form, contact your prescriber.
• You must not take SORIATANE if you are pregnant or might become
pregnant during treatment or at any time for at least 3 years after you
stop treatment because SORIATANE can cause severe birth defects.
• During treatment with SORIATANE and for 2 months after you stop
treatment with SORIATANE, you must avoid drinks, foods, and all
medicines that contain alcohol. This includes over-the-counter products
that contain alcohol. Avoiding alcohol is very important, because alcohol
changes SORIATANE into a drug that may take longer than 3 years to leave your
body. The chance of birth defects may last longer than 3 years if you swallow
any form of alcohol during treatment with SORIATANE and for 2 months after
you stop taking SORIATANE.
• You and your prescriber must be sure you are not pregnant before you
start therapy with SORIATANE. You must have negative results from 2
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pregnancy tests before you start treatment with SORIATANE. A negative
result shows you are not pregnant. Because it takes a few days after pregnancy
begins for a test to show that you are pregnant, the first negative test may not
ensure you are not pregnant. Do not start SORIATANE until you have negative
results from 2 pregnancy tests.
• The first pregnancy test will be done at the time you and your prescriber
decide if SORIATANE might be right for you.
• The second pregnancy test will usually be done during the first 5 days of
your menstrual period, right before you plan to start SORIATANE. Your
prescriber may suggest another time.
• After you start taking SORIATANE, you must have a pregnancy test repeated
each month that you are taking SORIATANE. This is to be sure that you are not
pregnant during treatment because SORIATANE can cause birth defects.
• For at least 3 years after stopping treatment with SORIATANE, you must have a
pregnancy test repeated every 3 months to make sure that you are not
pregnant.
• Discuss effective birth control (contraception) with your prescriber. You
must use 2 effective forms of birth control (contraception) at the same
time during all of the following:
o for at least 1 month before beginning treatment with SORIATANE
o during treatment with SORIATANE
o for at least 3 years after stopping treatment with SORIATANE
• If you are sexually active, you must use 2 effective forms of birth
control (contraception) at the same time even if you think you cannot
become pregnant, unless 1 of the following is true for you:
o You had your womb (uterus) removed during an operation (a
hysterectomy).
o Your prescriber said you have gone completely through menopause
(the “change of life”).
• You can get a free birth control counseling session and pregnancy
testing from a prescriber or family planning expert. Your prescriber can
give you a SORIATANE Patient Referral Form for this free session.
• You must use 2 effective forms of birth control (contraception) at the
same time while you are on treatment with SORIATANE. You must use
birth control for at least 1 month before you start taking SORIATANE,
during treatment, and at least 3 years after you stop treatment with
SORIATANE.
The following are considered effective forms of birth control:
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Primary Forms:
having your tubes tied (tubal ligation)
partner’s vasectomy
IUD (Intrauterine device)
birth control pills that contain both estrogen and progestin (combination oral
contraceptives)
hormonal birth control products that are injected, implanted, or inserted in
your body
birth control patch
Secondary Forms (use with a Primary Form):
diaphragms with spermicide
latex condoms (with or without spermicide)
cervical caps with spermicide
At least 1 of your 2 methods of birth control must be a primary form.
• If you have sex at any time without using 2 effective forms of birth
control (contraception) at the same time, or if you get pregnant or miss
your period, stop using SORIATANE and call your prescriber right away.
• Consider “Emergency Contraception” (EC) if you have sex with a male
without correctly using 2 effective forms of birth control
(contraception) at the same time. EC is also called “emergency birth control”
or the “morning after” pill. Contact your prescriber as soon as possible if you
have sex without using 2 effective forms of birth control (contraception) at the
same time, because EC works best if it is used within 1 or 2 days after sex. EC is
not a replacement for your usual 2 effective forms of birth control
(contraception) because it is not as effective as regular birth control methods.
You can get EC from private doctors or nurse practitioners, women’s health
centers, or hospital emergency rooms. You can get the name and phone number
of EC providers nearest you by calling the free Emergency Contraception Hotline
at 1-888-668-2528 (1-888-NOT-2-LATE).
• Stop taking SORIATANE right away and contact your prescriber if you
get pregnant while taking SORIATANE or at any time for at least 3 years
after treatment has stopped. You need to discuss the possible effects on
the unborn baby with your prescriber.
• If you do become pregnant while taking SORIATANE or at any time for
at least 3 years after stopping SORIATANE, you should report your
pregnancy to Stiefel Laboratories, Inc. at 1-888-784-3335 (1-888
STIEFEL) or directly to the Food and Drug Administration (FDA)
MedWatch program at 1-800-FDA-1088. Your name will be kept in private
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(confidential). The information you share will help the FDA and the manufacturer
evaluate the Pregnancy Prevention Program for SORIATANE.
• Do not take SORIATANE if you are breastfeeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
What should males know before taking SORIATANE?
Small amounts of SORIATANE are found in the semen of males taking SORIATANE.
Based upon available information, it appears that these small amounts of
SORIATANE in semen pose little, if any, risk to an unborn child while a male patient
is taking the drug or after it is discontinued. Discuss any concerns you have about
this with your prescriber.
All patients should read the rest of this Medication Guide.
What is SORIATANE?
SORIATANE is a medicine used to treat severe forms of psoriasis in adults. Psoriasis
is a skin disease that causes cells in the outer layer of the skin to grow faster than
normal and pile up on the skin’s surface. In the most common type of psoriasis, the
skin becomes inflamed and produces red, thickened areas, often with silvery scales.
Because SORIATANE can have serious side effects, you should talk with your
prescriber about whether possible benefits of SORIATANE outweigh its possible
risks.
SORIATANE may not work right away. You may have to wait 2 to 3 months before
you get the full benefit of SORIATANE. Psoriasis gets worse for some patients when
they first start treatment with SORIATANE.
SORIATANE has not been studied in children.
Who should not take SORIATANE?
• Do NOT take SORIATANE if you can get pregnant. Do not take SORIATANE
if you are pregnant or might get pregnant during SORIATANE treatment or at
any time for at least 3 years after you stop SORIATANE treatment (see “What
are the important warnings and instructions for females taking SORIATANE?”).
• Do NOT take SORIATANE if you are breastfeeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
• Do NOT take SORIATANE if you have severe liver or kidney disease.
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• Do NOT take SORIATANE if you have repeated high blood lipids (fat in
the blood).
• Do NOT take SORIATANE if you take these medicines:
o methotrexate
o tetracyclines
The use of these medicines with SORIATANE may cause serious side effects.
• Do NOT take SORIATANE if you are allergic to acitretin, the active
ingredient in SORIATANE, to any of the other ingredients in SORIATANE (see the
end of this Medication Guide for a list of all the ingredients in SORIATANE), or to
any medicines that are like SORIATANE. Ask your prescriber or pharmacist if any
medicines you are allergic to are like SORIATANE.
Tell your prescriber if you have or ever had:
• diabetes or high blood sugar
• liver problems
• kidney problems
• high cholesterol or high triglycerides (fat in the blood)
• heart disease
• depression
• alcoholism
• an allergic reaction to a medication
Your prescriber needs this information to decide if SORIATANE is right for you and
to know what dose is best for you.
Tell your prescriber about all the medicines you take, including prescription
and over-the-counter medicines, vitamins, and herbal supplements. Some
medicines can cause serious side effects if taken while you also take SORIATANE.
Some medicines may affect how SORIATANE works, or SORIATANE may affect how
your other medicines work. Be especially sure to tell your prescriber if you are
taking the following medicines:
• methotrexate
• tetracyclines
• glyburide
• phenytoin
• vitamin A supplements
• progestin-only oral contraceptives (“minipills”)
• TEGISON® or TIGASON (etretinate). Tell your prescriber if you have ever taken
this medicine in the past.
• St. John’s wort herbal supplement
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Tell your prescriber if you are getting phototherapy treatment. Your doses of
phototherapy may need to be changed to prevent a burn.
How should I take SORIATANE?
• Take SORIATANE with food.
• Be sure to take your medicine as prescribed by your prescriber. The dose of
SORIATANE varies from patient to patient. The number of capsules you must
take is chosen specially for you by your prescriber. This dose may change during
treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose and
resume your normal schedule.
• If you take too much SORIATANE (overdose), call your local poison control
center or emergency room.
You should have blood tests for liver function, cholesterol, and triglycerides before
starting treatment and during treatment to check your body’s response to
SORIATANE. Your prescriber may also do other tests.
Once you stop taking SORIATANE, your psoriasis may return. Do not treat this new
psoriasis with leftover SORIATANE. It is important to see your prescriber again for
treatment recommendations because your situation may have changed.
What should I avoid while taking SORIATANE?
• Avoid pregnancy. See “What is the most important information I should know
about SORIATANE?”, and “What are the important warnings and instructions for
females taking SORIATANE?”
• Avoid breastfeeding. See “What are the important warnings and instructions
for females taking SORIATANE?”
• Avoid alcohol. Females must avoid drinks, foods, medicines, and over-the
counter products that contain alcohol. The risk of birth defects may continue for
longer than 3 years if you swallow any form of alcohol during treatment with
SORIATANE and for 2 months after stopping SORIATANE (see “What are the
important warnings and instructions for females taking SORIATANE?”).
• Avoid giving blood. Do not donate blood while you are taking SORIATANE
and for at least 3 years after stopping treatment with SORIATANE.
SORIATANE in your blood can harm an unborn baby if your blood is given to a
pregnant woman. SORIATANE does not affect your ability to receive a blood
transfusion.
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• Avoid progestin-only birth control pills (“minipills”). This type of birth
control pill may not work while you take SORIATANE. Ask your prescriber if you
are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop
taking SORIATANE and call your prescriber if this occurs (see “Serious side
effects”).
• Avoid non-medical ultraviolet (UV) light. SORIATANE can make your skin
more sensitive to UV light. Do not use sunlamps, and avoid sunlight as much as
possible. If you are taking light treatment (phototherapy), your prescriber may
need to change your light dosages to avoid burns.
• Avoid dietary supplements containing vitamin A. SORIATANE is related to
vitamin A. Therefore, do not take supplements containing vitamin A, because
they may add to the unwanted effects of SORIATANE. Check with your
prescriber or pharmacist if you have any questions about vitamin supplements.
• DO NOT SHARE SORIATANE with anyone else, even if they have the
same symptoms. Your medicine may harm them or their unborn child.
What are the possible side effects of SORIATANE?
SORIATANE can cause serious side effects. See “What is the most important
information I should know about SORIATANE?” and “What are the
important warnings and instructions for females taking SORIATANE?”
Stop taking SORIATANE and call your prescriber right away if you get the
following signs or symptoms of possible serious side effects:
• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be
signs of increased brain pressure that can lead to blindness or even death.
• Vision problems. Decreased vision in the dark (night blindness). Since
this can start suddenly, you should be very careful when driving at night. This
problem usually goes away when SORIATANE treatment stops. Stop taking
SORIATANE and call your prescriber if you develop any vision problems or eye
pain.
• Depression. There have been some reports of patients developing mental
problems including a depressed mood, aggressive feelings, or thoughts of
ending their own life (suicide). These events, including suicidal behavior, have
been reported in patients taking other drugs similar to SORIATANE as well as
patients taking SORIATANE. Since other things may have contributed to these
problems, it is not known if they are related to SORIATANE.
• Aches or pains in your bones, joints, muscles, or back, trouble moving,
or loss of feeling in your hands or feet. These can be signs of abnormal
changes to your bones or muscles.
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• Frequent urination, great thirst or hunger. SORIATANE can affect blood
sugar control, even if you do not already have diabetes. These are some of the
signs of high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble
speaking, or swelling of a leg. These may be signs of a heart attack,
blood clots, or stroke. SORIATANE can cause serious changes in blood fats
(lipids). It is possible for these changes to cause blood vessel blockages that
lead to heart attacks, strokes, or blood clots.
• Blood vessel problems. SORIATANE can cause fluid to leak out of your blood
vessels into your body tissues. Call your prescriber right away if you have
any of the following symptoms: sudden swelling in one part of your body or
all over your body, weight gain, fever, lightheadedness or feeling faint, or
muscle aches. If this happens, your prescriber will tell you to stop taking
SORIATANE.
• Serious allergic reactions. See “Who should not take SORIATANE?” Serious
allergic reactions can happen during treatment with SORIATANE. Call your
prescriber right away if you get any of the following symptoms of an
allergic reaction: hives, itching, swelling of your face, mouth, or tongue, or
problems breathing. If this happens, stop taking SORIATANE and do not
take it again.
• Serious skin problems. SORIATANE can cause skin problems that can begin in
a small area and then spread over large areas of your body. Call your
prescriber right away if your skin becomes red and swollen (inflamed),
you have peeling of your skin, or your skin becomes itchy and painful.
You should stop SORIATANE if this happens.
Common side effects
If you develop any of these side effects or any unusual reaction, check with your
prescriber to find out if you need to change the amount of SORIATANE you take.
These side effects usually get better if the dose of SORIATANE is reduced or
SORIATANE is stopped.
• Chapped lips, peeling fingertips, palms, and soles, itching, scaly skin all
over, weak nails, sticky or fragile (weak) skin, runny or dry nose, or
nosebleeds. Your prescriber or pharmacist can recommend a lotion or cream to
help treat drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
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• Hair loss. Most patients have some hair loss, but this condition varies among
patients. No one can tell if you will lose hair, how much hair you may lose or if
and when it may grow back. You may also lose your eyelashes.
• Dry eyes. SORIATANE may dry your eyes. Wearing contact lenses may be
uncomfortable during and after treatment with SORIATANE because of the dry
feeling in your eyes. If this happens, remove your contact lenses and call your
prescriber. Also read the section about vision under “Serious side effects”.
• Rise in blood fats (lipids). SORIATANE can cause your blood fats (lipids) to
rise. Most of the time this is not serious. But sometimes the increase can
become a serious problem (see information under “Serious side effects”). You
should have blood tests as directed by your prescriber.
Psoriasis gets worse for some patients when they first start treatment with
SORIATANE. Some patients have more redness or itching. If this happens, tell your
prescriber. These symptoms usually get better as treatment continues, but your
prescriber may need to change the amount of your medicine.
These are not all the possible side effects of SORIATANE. For more information, ask
your prescriber or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store SORIATANE?
Keep SORIATANE away from sunlight, high temperature, and humidity.
Keep SORIATANE and all medicines out of the reach of children.
What are the ingredients in SORIATANE?
Active ingredient: acitretin.
Inactive ingredients: black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate. Gelatin capsule
shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide.
They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate
calcium disodium.
General information about the safe and effective use of SORIATANE
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use SORIATANE for a condition for which it was not
prescribed. Do not give SORIATANE to other people, even if they have the same
symptoms that you have.
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This Medication Guide summarizes the most important information about
SORIATANE. If you would like more information, talk with your prescriber. You can
ask your pharmacist or prescriber for information about SORIATANE that is written
for health professionals.
For more information about SORIATANE call 1-888-784-3335 or go to
www.soriatane.com.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Manufactured for company logo
Stiefel Laboratories, Inc.
Research Triangle Park, NC 27709
Revised May/2014
TEGISON® is a registered trademark of Hoffmann-La Roche Inc.
Do Your P.A.R.T. is a trademark and SORIATANE is a registered trademark of
Stiefel Laboratories, Inc.
©2014, Stiefel Laboratories, Inc.
SRN:XMG
Reference ID: 3505985
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:00.572888
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019821s024lbl.pdf', 'application_number': 19821, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
11,744
|
SORIATANE®
(acitretin)
Capsules avoid pregnancy logo
CONTRAINDICATIONS AND WARNINGS: Pregnancy
SORIATANE must not be used by females who are pregnant, or who intend to become
pregnant during therapy or at any time for at least 3 years following discontinuation of
therapy. SORIATANE also must not be used by females who may not use reliable
contraception while undergoing treatment and for at least 3 years following
discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON®), and
major human fetal abnormalities have been reported with the administration of acitretin
and etretinate. Potentially, any fetus exposed can be affected.
Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been
associated with the formation of etretinate, which has a significantly longer elimination
half-life than acitretin. Because the longer elimination half-life of etretinate would increase
the duration of teratogenic potential for female patients, ethanol must not be ingested by
female patients of childbearing potential either during treatment with SORIATANE or for
2 months after cessation of therapy. This allows for elimination of acitretin, thus removing
the substrate for transesterification to etretinate. The mechanism of the metabolic process
for conversion of acitretin to etretinate has not been fully defined. It is not known whether
substances other than ethanol are associated with transesterification.
Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats
at oral doses of 0.6, 3, and 15 mg per kg, respectively. These doses are approximately 0.2,
0.3, and 3 times the maximum recommended therapeutic dose, respectively, based on a mg
per-m2 comparison.
Major human fetal abnormalities associated with acitretin and/or etretinate
administration have been reported including meningomyelocele; meningoencephalocele;
multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges;
malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial
volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae.
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SORIATANE should be prescribed only by those who have special competence in the
diagnosis and treatment of severe psoriasis, are experienced in the use of systemic
retinoids, and understand the risk of teratogenicity.
Because of the teratogenicity of SORIATANE, a program called the Do Your P.A.R.T.
program, Pregnancy Prevention Actively Required During and After Treatment, has been
developed to educate women of childbearing potential and their healthcare providers about
the serious risks associated with acitretin and to help prevent pregnancies from occurring
with the use of this drug and for 3 years after its discontinuation. The Do Your P.A.R.T.
program requirements are described below and program materials are available at
www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784
3335 (1-888-STIEFEL) (see also PRECAUTIONS section).
Important Information for Women of Childbearing Potential:
SORIATANE should be considered only for women with severe psoriasis unresponsive
to other therapies or whose clinical condition contraindicates the use of other treatments.
Females of reproductive potential must not be given a prescription for SORIATANE
until pregnancy is excluded. SORIATANE is contraindicated in females of reproductive
potential unless the patient meets ALL of the following conditions:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at
least 25 mIU per mL before receiving the initial prescription for SORIATANE. The
first test (a screening test) is obtained by the prescriber when the decision is made to
pursue therapy with SORIATANE. The second pregnancy test (a confirmation test)
should be done during the first 5 days of the menstrual period immediately
preceding the beginning of therapy with SORIATANE. For patients with
amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception
[birth control] simultaneously). If the second pregnancy test is negative, initiation of
treatment with SORIATANE should begin within 7 days of the specimen collection.
SORIATANE should be limited to a monthly supply.
• Must have a pregnancy test with a sensitivity of at least 25 mIU per mL repeated
every month during treatment with SORIATANE. The patient must have a negative
result from a urine or serum pregnancy test before receiving a prescription for
SORIATANE. To encourage compliance with this recommendation, a monthly
supply of the drug should be prescribed. For at least 3 years after discontinuing
therapy with SORIATANE, a pregnancy test must be repeated every 3 months.
• Must have selected and have committed to use 2 effective forms of contraception
(birth control) simultaneously, at least 1 of which must be a primary form, unless
absolute abstinence is the chosen method, or the patient has undergone a
hysterectomy or is clearly postmenopausal.
• Patients must use 2 effective forms of contraception (birth control) simultaneously
for at least 1 month prior to initiation of therapy with SORIATANE, during
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therapy with SORIATANE, and for at least 3 years after discontinuing therapy with
SORIATANE. A Contraception Counseling Referral Form is available so that
patients can receive an initial free contraception counseling session and pregnancy
testing. Counseling about contraception and behaviors associated with an increased
risk of pregnancy must be repeated on a monthly basis by the prescriber during
therapy with SORIATANE and every 3 months for at least 3 years following
discontinuation of SORIATANE.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products.
Secondary forms of contraception include condoms (with or without spermicide),
diaphragms and cervical caps (which must be used with a spermicide), and vaginal
sponges (contains spermicide).
Any birth control method can fail. Therefore, it is critically important that women
of childbearing potential use 2 effective forms of contraception (birth control)
simultaneously. It has not been established if there is a pharmacokinetic interaction
between acitretin and combined oral contraceptives. However, it has been
established that acitretin interferes with the contraceptive effect of microdosed
progestin preparations.1 Microdosed “minipill” progestin preparations are not
recommended for use with SORIATANE. It is not known whether other progestin
only contraceptives, such as implants and injectables, are adequate methods of
contraception during acitretin therapy. Prescribers are advised to consult the package
insert of any medication administered concomitantly with hormonal contraceptives,
since some medications may decrease the effectiveness of these birth control
products. Patients should be prospectively cautioned not to self-medicate with the
herbal supplement St. John’s wort because a possible interaction has been suggested
with hormonal contraceptives based on reports of breakthrough bleeding on oral
contraceptives shortly after starting St. John’s wort. Pregnancies have been
reported by users of combined hormonal contraceptives who also used some form of
St. John’s wort (see PRECAUTIONS).
• Must have signed a Patient Agreement/Informed Consent for Female Patients that
contains warnings about the risk of potential birth defects if the fetus is exposed to
SORIATANE, about contraceptive failure, about the fact that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2
months after treatment with SORIATANE has been discontinued, and about
preventing pregnancy while taking SORIATANE and for at least 3 years after
discontinuing SORIATANE.
If pregnancy does occur during therapy with SORIATANE or at any time for at
least 3 years following discontinuation of SORIATANE, the prescriber and patient
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should discuss the possible effects on the pregnancy. The available information is as
follows:
Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated
during pregnancy. The risk of severe fetal malformations is well established when
systemic retinoids are taken during pregnancy. Pregnancy must also be prevented
after stopping acitretin therapy, while the drug is being eliminated to below a
threshold blood concentration that would be associated with an increased incidence
of birth defects. Because this threshold has not been established for acitretin in
humans and because elimination rates vary among patients, the duration of
posttherapy contraception to achieve adequate elimination cannot be calculated
precisely. It is strongly recommended that contraception be continued for at least 3
years after stopping treatment with acitretin, based on the following considerations:
o In the absence of transesterification to form etretinate, greater than 98% of
the acitretin would be eliminated within 2 months, assuming a mean
elimination half-life of 49 hours.
o In cases where etretinate is formed, as has been demonstrated with
concomitant administration of acitretin and ethanol,
♦ greater than 98% of the etretinate formed would be eliminated in 2 years,
assuming a mean elimination half-life of 120 days.
♦ greater than 98% of the etretinate formed would be eliminated in 3 years,
based on the longest demonstrated elimination half-life of 168 days.
However, etretinate was found in plasma and subcutaneous fat in one
patient reported to have had sporadic alcohol intake, 52 months after she
stopped acitretin therapy.2
• Severe birth defects have been reported where conception occurred during the time
interval when the patient was being treated with acitretin and/or etretinate. In
addition, severe birth defects have also been reported when conception occurred
after the mother completed therapy. These cases have been reported both
prospectively (before the outcome was known) and retrospectively (after the
outcome was known). The events below are listed without distinction as to whether
the reported birth defects are consistent with retinoid-induced embryopathy or not.
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♦ There have been 318 prospectively reported cases involving pregnancies
and the use of etretinate, acitretin, or both. In 238 of these cases, the
conception occurred after the last dose of etretinate (103 cases), acitretin
(126), or both (9). Fetal outcome remained unknown in approximately
one-half of these cases, of which 62 were terminated and 14 were
spontaneous abortions. Fetal outcome is known for the other 118 cases
and 15 of the outcomes were abnormal (including cases of absent
hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia, limb
malformation, neonatal apnea/anemia, neonatal ichthyosis, placental
disorder/death, undescended testicle, and 5 cases of premature birth). In
the 126 prospectively reported cases where conception occurred after the
last dose of acitretin only, 43 cases involved conception at least 1 year but
less than 2 years after the last dose. There were 3 reports of abnormal
outcomes out of these 43 cases (involving limb malformation, GI tract
malformations, and premature birth). There were only 4 cases where
conception occurred at least 2 years after the last dose but there were no
reports of birth defects in these cases.
♦ There is also a total of 35 retrospectively reported cases where conception
occurred at least 1 year after the last dose of etretinate, acitretin, or both.
From these cases there are 3 reports of birth defects when the conception
occurred at least 1 year but less than 2 years after the last dose of
acitretin (including heart malformations, Turner’s Syndrome, and
unspecified congenital malformations) and 4 reports of birth defects
when conception occurred 2 or more years after the last dose of acitretin
(including foot malformation, cardiac malformations [2 cases], and
unspecified neonatal and infancy disorder). There were 3 additional
abnormal outcomes in cases where conception occurred 2 or more years
after the last dose of etretinate (including chromosome disorder, forearm
aplasia, and stillbirth).
♦ Females who have taken TEGISON (etretinate) must continue to follow
the contraceptive recommendations for TEGISON. TEGISON is no
longer marketed in the US; for information, call Stiefel at 1-888-784-3335
(1-888-STIEFEL).
♦ Patients should not donate blood during and for at least 3 years following
the completion of therapy with SORIATANE because women of
childbearing potential must not receive blood from patients being treated
with SORIATANE.
Important Information for Males Taking SORIATANE:
Patients should not donate blood during and for at least 3 years following therapy
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with SORIATANE because women of childbearing potential must not receive blood
from patients being treated with SORIATANE.
•
Samples of seminal fluid from 3 male patients treated with acitretin and 6 male
patients treated with etretinate have been assayed for the presence of acitretin. The
maximum concentration of acitretin observed in the seminal fluid of these men was
12.5 ng per mL. Assuming an ejaculate volume of 10 mL, the amount of drug
transferred in semen would be 125 ng, which is 1/200,000 of a single 25-mg capsule.
Thus, although it appears that residual acitretin in seminal fluid poses little, if any,
risk to a fetus while a male patient is taking the drug or after it is discontinued, the
no-effect limit for teratogenicity is unknown and there is no registry for birth
defects associated with acitretin. The available data are as follows:
There have been 25 cases of reported conception when the male partner was taking
acitretin. The pregnancy outcome is known in 13 of these 25 cases. Of these, 9 reports
were retrospective and 4 were prospective (meaning the pregnancy was reported prior to
knowledge of the outcome)3 .
For All Patients: A SORIATANE MEDICATION GUIDE MUST BE GIVEN TO THE
PATIENT EACH TIME SORIATANE IS DISPENSED, AS REQUIRED BY LAW.
DESCRIPTION
SORIATANE (acitretin), a retinoid, is available in 10-mg, 17.5-mg, and 25-mg gelatin
capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6
trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is
related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder
with a molecular weight of 326.44. The structural formula is: structural formula
Each capsule contains acitretin, black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate.
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Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium
dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium
disodium.
CLINICAL PHARMACOLOGY
The mechanism of action of SORIATANE is unknown.
Pharmacokinetics: Absorption: Oral absorption of acitretin is optimal when given with
food. For this reason, acitretin was given with food in all of the following trials. After
administration of a single 50-mg oral dose of acitretin to 18 healthy subjects, maximum plasma
concentrations ranged from 196 to 728 ng per mL (mean: 416 ng per mL) and were achieved in 2
to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with
increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the
administered dose was absorbed after a single 50-mg dose of acitretin was given to 12 healthy
subjects.
Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism: (See Pharmacokinetic Drug Interactions: Ethanol.) Following oral
absorption, acitretin undergoes extensive metabolism and interconversion by simple
isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent
compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both
parent compound and isomer are further metabolized into chain-shortened breakdown products
and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-
state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3
weeks.
Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin
are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal
elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to
96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157
hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
Special Populations: Psoriasis: In an 8-week trial of acitretin pharmacokinetics in
subjects with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose-
proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma
concentrations were nonmeasurable (<4 ng per mL) in all subjects 3 weeks after cessation of
therapy.
Elderly: In a multiple-dose trial in healthy young (n = 6) and elderly (n = 8) subjects, a 2
fold increase in acitretin plasma concentrations were seen in elderly subjects, although the
elimination half-life did not change.
Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in
subjects with end-stage renal failure (n = 6) when compared with age-matched controls,
following single 50-mg oral doses. Acitretin was not removed by hemodialysis in these subjects.
Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND
WARNINGS and PRECAUTIONS: Drug Interactions): In studies of in vivo
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pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine,
digoxin, phenprocoumon, or glyburide.
Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-
life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way
crossover trial, all 10 subjects formed etretinate with concurrent ingestion of a single 100-mg
oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately
1.4 g per kg body weight). A mean peak etretinate concentration of 59 ng per mL (range: 22 to
105 ng per mL) was observed, and extrapolation of AUC values indicated that the formation of
etretinate in this trial was comparable to a single 5-mg oral dose of etretinate. There was no
detectable formation of etretinate when a single 100-mg oral dose of acitretin was administered
without concurrent ethanol ingestion, although the formation of etretinate without concurrent
ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS).
Of 93 evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to
80 mg per day), 16% had measurable etretinate levels (> 5 ng per mL).
Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial
the apparent mean terminal half-life after 6 months of therapy was approximately 120 days
(range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had
detectable serum drug levels (in the range of 0.5 to 12 ng per mL) 2.1 to 2.9 years after therapy
was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.
Progestin-only Contraceptives: It has not been established if there is a
pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has
been established that acitretin interferes with the contraceptive effect of microdosed progestin
preparations.1 Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE. It is not known whether other progestin-only contraceptives, such as implants and
injectables, are adequate methods of contraception during acitretin therapy.
CLINICAL STUDIES
In 2 double-blind, placebo-controlled trials, SORIATANE was administered once daily to
subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8
weeks (see Table 1) subjects treated in Trial A with 50 mg of SORIATANE per day showed
significant improvements (P ≤0.05) relative to baseline and to placebo in the physician’s global
evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In
Trial B, differences from baseline and from placebo were statistically significant (P ≤0.05) for all
variables at both the 25-mg and 50-mg doses; it should be noted for Trial B that no statistical
adjustment for multiplicity was carried out.
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Table 1. Summary of the Efficacy Results of the 8-Week Double-Blind Phase of Trials A
and B of SORIATANE
Efficacy Variables
Trial A
Trial B
Total Daily Dose
Total Daily Dose
Placebo
(N = 29)
50 mg
(N = 29)
Placebo
(N = 72)
25 mg
(N = 74)
50 mg
(N = 71)
Physician’s
Global Evaluation
Baseline
Mean Change
After 8 Weeks
4.62
−0.29
4.55
−2.00a
4.43
−0.06
4.37
−1.06a
4.49
−1.57a
Scaling
Baseline
Mean Change
After 8 Weeks
4.10
−0.22
3.76
−1.62a
3.97
−0.21
4.11
−1.50a
4.10
−1.78a
Thickness
Baseline
Mean Change
After 8 Weeks
4.10
−0.39
4.10
−2.10 a
4.03
−0.18
4.11
−1.43 a
4.20
−2.11 a
Erythema
Baseline
Mean Change
After 8 Weeks
4.21
−0.33
4.59
−2.10a
4.42
−0.37
4.24
−1.12a
4.45
−1.65a
a Values were statistically significantly different from placebo and from baseline (P ≤0.05). No
adjustment for multiplicity was done for Trial B.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
A subset of 141 subjects from both pivotal Trials A and B continued to receive SORIATANE in
an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as
indicated in Table 2, were significantly improved (P ≤0.01) from baseline, including extent of
psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.
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Table 2. Summary of the First Course of Therapy with SORIATANE (24 Weeks)
Variables
Trial A
Trial B
Mean Total Daily Dose of SORIATANE (mg)
42.8
43.1
Mean Duration of Therapy (Weeks)
21.1
22.6
Physician’s Global Evaluation
Baseline
Mean Change From Baseline
N = 39
4.51
−2.26a
N = 98
4.43
−2.60a
Scaling
Baseline
Mean Change From Baseline
N = 59
3.97
−2.15a
N = 132
4.07
−2.42a
Thickness
Baseline
Mean Change From Baseline
N = 59
4.00
−2.44 a
N = 132
4.12
−2.66 a
Erythema
Baseline
Mean Change From Baseline
N = 59
4.35
−2.31a
N = 132
4.33
−2.29a
a Indicates that the difference from baseline was statistically significant (P ≤0.01).
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness,
erythema, and the physician’s global evaluation of the current status of the disease. Ratings of
scaling, erythema, and lesion thickness, and the ratings of the global assessments were made
using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 =
moderate-severe, 6 = severe).
All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated
for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a
small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course
of therapy (for a total of 18 months of treatment).
INDICATIONS AND USAGE
SORIATANE is indicated for the treatment of severe psoriasis in adults. Because of
significant adverse effects associated with its use, SORIATANE should be prescribed only by
those knowledgeable in the systemic use of retinoids. In females of reproductive potential,
SORIATANE should be reserved for non-pregnant patients who are unresponsive to other
therapies or whose clinical condition contraindicates the use of other treatments (see boxed
CONTRAINDICATIONS AND WARNINGS — SORIATANE can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses,
when clinically indicated, have produced efficacy results similar to the initial course of therapy.
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CONTRAINDICATIONS
Pregnancy Category X: (See boxed CONTRAINDICATIONS AND WARNINGS.)
SORIATANE is contraindicated in patients with severely impaired liver or kidney function
and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS:
Hepatotoxicity, WARNINGS: Lipids and Possible Cardiovascular Effects, and
PRECAUTIONS).
An increased risk of hepatitis has been reported to result from combined use of methotrexate
and etretinate. Consequently, the combination of methotrexate with SORIATANE is also
contraindicated (see PRECAUTIONS: Drug Interactions).
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri).
SORIATANE is contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to
the preparation (acitretin or excipients) or to other retinoids.
WARNINGS
(See also boxed CONTRAINDICATIONS AND WARNINGS.)
Hepatotoxicity: Of the 525 subjects treated in US clinical trials, 2 had clinical jaundice
with elevated serum bilirubin and transaminases considered related to treatment with
SORIATANE. Liver function test results in these subjects returned to normal after
SORIATANE was discontinued. Two of the 1,289 subjects treated in European clinical
trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects
revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial
of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject
showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal
tracts compatible with acute reversible hepatic injury. The subject's transaminase levels
returned to normal 2 months after SORIATANE was discontinued.
The potential of therapy with SORIATANE to induce hepatotoxicity was prospectively
evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and
posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings
before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%)
improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6
subjects, the classification changed from class 0 (no pathology) to class I (normal fatty
infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the
change was from class I to class II (fatty infiltration, nuclear variability, portal
inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was
from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found
between liver function test result abnormalities and the change in liver biopsy status, and
no cumulative dose relationship was found.
Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in
approximately 1 in 3 subjects treated with SORIATANE. Of the 525 subjects treated in
clinical trials in the US, treatment was discontinued in 20 (3.8%) due to elevated liver
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function test results. If hepatotoxicity is suspected during treatment with SORIATANE, the
drug should be discontinued and the etiology further investigated.
Ten of 652 subjects treated in US clinical trials of etretinate, of which acitretin is the
active metabolite, had clinical or histologic hepatitis considered to be possibly or probably
related to etretinate treatment.
There have been reports of hepatitis-related deaths worldwide; a few of these subjects
had received etretinate for a month or less before presenting with hepatic symptoms or
signs.
Skeletal Abnormalities: In adults receiving long-term treatment with SORIATANE,
appropriate examinations should be periodically performed in view of possible ossification
abnormalities (see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic
bony abnormality in adults is low, periodic radiography is only warranted in the presence of
symptoms or long-term use of SORIATANE. If such disorders arise, the continuation of therapy
should be discussed with the patient on the basis of a careful risk/benefit analysis. In clinical
trials with SORIATANE, subjects were prospectively evaluated for evidence of development or
change in bony abnormalities of the vertebral column, knees, and ankles.
Of 380 subjects treated with SORIATANE, 15% had preexisting abnormalities of the spine
which showed new changes or progression of preexisting findings. Changes included
degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis,
ligament calcification, and narrowing and destruction of a cervical disc space. De novo changes
(formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.
Six of 128 subjects treated with SORIATANE showed abnormalities in the knees and ankles
before treatment that progressed during treatment. In 5, these changes involved the formation of
additional spurs or enlargement of existing spurs. The sixth subject had degenerative joint
disease which worsened. No subjects developed spurs de novo. Clinical complaints did not
predict radiographic changes.
Lipids and Possible Cardiovascular Effects: Blood lipid determinations should be
performed before SORIATANE is administered and again at intervals of 1 to 2 weeks until the
lipid response to the drug is established, usually within 4 to 8 weeks. In subjects receiving
SORIATANE during clinical trials, 66% and 33% experienced elevation in triglycerides and
cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of
subjects. These effects of SORIATANE were generally reversible upon cessation of therapy.
Subjects with an increased tendency to develop hypertriglyceridemia included those with
disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a
familial history of these conditions. Because of the risk of hypertriglyceridemia, serum lipids
must be more closely monitored in high-risk patients and during long-term treatment.
Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status.
Although no causal relationship has been established, there have been postmarketing reports of
acute myocardial infarction or thromboembolic events in patients on therapy with SORIATANE.
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In addition, elevation of serum triglycerides to greater than 800 mg per dL has been associated
with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of
SORIATANE, or drug therapy should be employed to control significant elevations of
triglycerides. If, despite these measures, hypertriglyceridemia and low HDL levels persist, the
discontinuation of SORIATANE should be considered.
Ophthalmologic Effects: The eyes and vision of 329 subjects treated with SORIATANE
were examined by ophthalmologists. The findings included dry eyes (23%), irritation of eyes
(9%), and brow and lash loss (5%). The following were reported in less than 5% of subjects:
Bell’s palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial
abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear
cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and
subepithelial corneal lesions.
Any patient treated with SORIATANE who is experiencing visual difficulties should
discontinue the drug and undergo ophthalmologic evaluation.
Pancreatitis: Lipid elevations occur in 25% to 50% of subjects treated with SORIATANE.
Triglyceride increases sufficient to be associated with pancreatitis are much less common,
although fatal fulminant pancreatitis has been reported. There have been rare reports of
pancreatitis during therapy with SORIATANE in the absence of hypertriglyceridemia.
Pseudotumor Cerebri: SORIATANE and other retinoids administered orally have been
associated with cases of pseudotumor cerebri (benign intracranial hypertension). Some of these
events involved concomitant use of isotretinoin and tetracyclines. However, the event seen in a
single patient receiving SORIATANE was not associated with tetracycline use. Early signs and
symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Patients
with these signs and symptoms should be examined for papilledema and, if present, should
discontinue SORIATANE immediately and be referred for neurological evaluation and care.
Since both SORIATANE and tetracyclines can cause increased intracranial pressure, their
combined use is contraindicated (see CONTRAINDICATIONS).
Capillary Leak Syndrome: Capillary leak syndrome, a potential manifestation of retinoic
acid syndrome, has been reported in patients receiving SORIATANE. Features of this syndrome
may include localized or generalized edema with secondary weight gain, fever, and hypotension.
Rhabdomyolysis and myalgias have been reported in association with capillary leak syndrome,
and laboratory tests may reveal neutrophilia, hypoalbuminemia, and an elevated hematocrit.
Discontinue SORIATANE if capillary leak syndrome develops during therapy.
Exfoliative Dermatitis/Erythroderma: Exfoliative dermatitis/erythroderma has been
reported in patients receiving SORIATANE. Discontinue SORIATANE if exfoliative
dermatitis/erythroderma occurs during therapy.
PRECAUTIONS
A description of the Do Your P.A.R.T. materials is provided below. The main goals of the
materials are to explain the program requirements, to reinforce the educational messages, and to
assess program effectiveness.
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The Do Your P.A.R.T. booklet includes:
• The Do Your P.A.R.T. Patient Brochure: information on the program requirements, risks of
acitretin, and the types of contraceptive methods
• The Contraception Counseling Referral Form for female patients who want to receive free
contraception counseling reimbursed by the manufacturer
• The Patient Agreement/Informed Consent for Female Patients form
• Medication Guide
The Do Your P.A.R.T. program also includes a voluntary patient survey for women of
childbearing potential to assess the effectiveness of the SORIATANE Pregnancy Prevention
Program Do Your P.A.R.T. Do Your P.A.R.T. Program materials are available at
www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784-3335
(1-888-STIEFEL).
Information for Patients:
(See Medication Guide for all patients and Patient Agreement/Informed Consent for
Female Patients at end of professional labeling.)
Patients should be instructed to read the Medication Guide supplied as required by law when
SORIATANE is dispensed.
Females of Reproductive Potential: SORIATANE can cause severe birth defects.
Female patients must not be pregnant when therapy with SORIATANE is initiated, they must not
become pregnant while taking SORIATANE and for at least 3 years after stopping
SORIATANE, so that the drug can be eliminated to below a blood concentration that would be
associated with an increased incidence of birth defects. Because this threshold has not been
established for acitretin in humans and because elimination rates vary among patients, the
duration of posttherapy contraception to achieve adequate elimination cannot be calculated
precisely (see boxed CONTRAINDICATIONS AND WARNINGS).
Females of reproductive potential should also be advised that they must not ingest
beverages or products containing ethanol while taking SORIATANE and for 2 months
after SORIATANE has been discontinued. This allows for elimination of the acitretin which
can be converted to etretinate in the presence of alcohol.
Female patients should be advised that any method of birth control can fail, including tubal
ligation, and that microdosed progestin “minipill” preparations are not recommended for use
with SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions).
Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel
0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during
acitretin treatment.2
Female patients should sign a consent form prior to beginning therapy with SORIATANE (see
boxed CONTRAINDICATIONS AND WARNINGS).
Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the
milk. There is one prospective case report where acitretin is reported to be excreted in human
milk. Therefore, nursing mothers should not receive SORIATANE prior to or during nursing
because of the potential for serious adverse reactions in nursing infants.
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All Patients: Depression and/or other psychiatric symptoms such as aggressive feelings
or thoughts of self-harm have been reported. These events, including self-injurious behavior,
have been reported in patients taking other systemically administered retinoids, as well as in
patients taking SORIATANE. Since other factors may have contributed to these events, it is not
known if they are related to SORIATANE. Patients should be counseled to stop taking
SORIATANE and notify their prescriber immediately if they experience psychiatric symptoms.
Patients should be advised that a transient worsening of psoriasis is sometimes seen during the
initial treatment period. Patients should be advised that they may have to wait 2 to 3 months
before they get the full benefit of SORIATANE, although some patients may achieve significant
improvements within the first 8 weeks of treatment as demonstrated in clinical trials.
Decreased night vision has been reported during therapy with SORIATANE. Patients should
be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night. Visual problems should be carefully monitored (see WARNINGS and
ADVERSE REACTIONS). Patients should be advised that they may experience decreased
tolerance to contact lenses during the treatment period and sometimes after treatment has
stopped.
Patients should not donate blood during and for at least 3 years following therapy because
SORIATANE can cause birth defects and women of childbearing potential must not receive
blood from patients being treated with SORIATANE.
Because of the relationship of SORIATANE to vitamin A, patients should be advised against
taking vitamin A supplements in excess of minimum recommended daily allowances to avoid
possible additive toxic effects.
Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical
UV exposure) because the effects of UV light are enhanced by retinoids.
Patients should be advised that they must not give their SORIATANE to any other person.
For Prescribers: SORIATANE has not been studied in and is not indicated for treatment of
acne.
Phototherapy: Significantly lower doses of phototherapy are required when
SORIATANE is used because effects on the stratum corneum induced by SORIATANE can
increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).
Drug Interactions: Ethanol: Clinical evidence has shown that etretinate can be formed with
concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND
WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Glyburide: In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood
glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7
subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not
detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under
treatment with SORIATANE is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Hormonal Contraceptives: It has not been established if there is a pharmacokinetic
interaction between acitretin and combined oral contraceptives. However, it has been established
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that acitretin interferes with the contraceptive effect of microdosed progestin “minipill”
preparations. Microdosed “minipill” progestin preparations are not recommended for use with
SORIATANE (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). It is
not known whether other progestin-only contraceptives, such as implants and injectables, are
adequate methods of contraception during acitretin therapy.
Methotrexate: An increased risk of hepatitis has been reported to result from combined use
of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is
also contraindicated (see CONTRAINDICATIONS).
Phenytoin: If acitretin is given concurrently with phenytoin, the protein binding of
phenytoin may be reduced.
Tetracyclines: Since both acitretin and tetracyclines can cause increased intracranial
pressure, their combined use is contraindicated (see CONTRAINDICATIONS and
WARNINGS: Pseudotumor Cerebri).
Vitamin A and Oral Retinoids: Concomitant administration of vitamin A and/or other oral
retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.
Other: There appears to be no pharmacokinetic interaction between acitretin and cimetidine,
digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of
anticoagulants of the coumarin type (warfarin) revealed no interaction.
Laboratory Tests: If significant abnormal laboratory results are obtained, either dosage
reduction with careful monitoring or treatment discontinuation is recommended, depending on
clinical judgment.
Blood Sugar: Some patients receiving retinoids have experienced problems with blood
sugar control. In addition, new cases of diabetes have been diagnosed during retinoid therapy,
including diabetic ketoacidosis. In diabetics, blood-sugar levels should be monitored very
carefully.
Lipids: In clinical trials, the incidence of hypertriglyceridemia was 66%,
hypercholesterolemia was 33%, and that of decreased HDL was 40%. Pretreatment and follow-
up measurements should be obtained under fasting conditions. It is recommended that these tests
be performed weekly or every other week until the lipid response to SORIATANE has stabilized
(see WARNINGS).
Liver Function Tests: Elevations of AST (SGOT), ALT (SGPT), or LDH were
experienced by approximately 1 in 3 patients treated with SORIATANE. It is recommended that
these tests be performed prior to initiation of therapy with SORIATANE, at 1- to 2-week
intervals until stable, and thereafter at intervals as clinically indicated (see
CONTRAINDICATIONS and boxed WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A
carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg per kg per day administered
7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed
that were considered to have been related to treatment with acitretin. An 80-week carcinogenesis
study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data
obtained during this study demonstrated that etretinate was metabolized to acitretin and that
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blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study,
an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several
different sites) was noted in male, but not female, mice at doses approximately one-half the
maximum recommended human therapeutic dose based on a mg-per-m2 comparison.
Mutagenesis: Acitretin was evaluated for mutagenic potential in the Ames test, in the
Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat
hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of
mutagenicity of acitretin was demonstrated in any of these assays.
Impairment of Fertility: In a fertility study in rats, the fertility of treated animals was not
impaired at the highest dosage of acitretin tested, 3 mg per kg per day (approximately one-half
the maximum recommended therapeutic dose based on a mg-per-m2 comparison). Chronic
toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic
arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then
30 mg per kg per day).
No decreases in sperm count or concentration and no changes in sperm motility or
morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of
keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12
weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or
FSH in any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis
in any of the 18 men where it was measured.4,5
Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed
CONTRAINDICATIONS AND WARNINGS).
In a study in which acitretin was administered to male rats only at a dosage of
5 mg per kg per day for 10 weeks (approximate duration of one spermatogenic cycle) prior to
and during mating with untreated female rats, no teratogenic effects were observed in the
progeny (see boxed CONTRAINDICATIONS AND WARNINGS for information about male
use of SORIATANE).
Nonteratogenic Effects: In rats dosed at 3 mg per kg per day (approximately one-half the
maximum recommended therapeutic dose based on a mg-per-m2 comparison), slightly decreased
pup survival and delayed incisor eruption were noted. At the next lowest dose tested,
1 mg per kg per day, no treatment-related adverse effects were observed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. No
clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments
and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and
premature epiphyseal closure have been reported in children taking other systemic retinoids,
including etretinate, a metabolite of SORIATANE. A causal relationship between these effects
and SORIATANE has not been established. While it is not known that these occurrences are
more severe or more frequent in children, there is special concern in pediatric patients because of
the implications for growth potential (see WARNINGS: Hyperostosis).
Geriatric Use: Clinical trials of SORIATANE did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently than younger subjects. Other
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reported clinical experience has not identified differences in responses between the elderly and
younger subjects. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in
acitretin plasma concentrations was seen in healthy elderly subjects compared with young
subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY:
Special Populations).
ADVERSE REACTIONS
Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the
mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many
of the clinical adverse reactions reported to date with administration of SORIATANE resemble
those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports: In addition to the events listed in the tables for
the clinical trials, the following adverse events have been identified during postapproval use of
SORIATANE. Because these events are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism (see WARNINGS),
stroke.
Immune System Disorders: Hypersensitivity, including angioedema and urticaria (see
CONTRAINDICATIONS).
Nervous System: Myopathy with peripheral neuropathy has been reported during therapy
with SORIATANE. Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts have been reported. These events,
including self-injurious behavior, have been reported in patients taking other systemically
administered retinoids, as well as in patients taking SORIATANE. Since other factors may have
contributed to these events, it is not known if they are related to SORIATANE (see
PRECAUTIONS).
Reproductive: Vulvo-vaginitis due to Candida albicans.
Skin and Appendages: Thinning of the skin, skin fragility, and scaling may occur all over
the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and
exfoliative dermatitis/erythroderma have been reported (see WARNINGS).
Vascular Disorders: Capillary leak syndrome (see WARNINGS).
Clinical Trials: During clinical trials with SORIATANE, 513 of 525 (98%) subjects reported a
total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely,
primarily because of adverse experiences involving the mucous membranes and skin. Three
subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung
cancer); the other subject died of an acute myocardial infarction, considered remotely related to
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drug therapy. In clinical trials, SORIATANE was associated with elevations in liver function test
results or triglyceride levels and hepatitis.
The tables below list by body system and frequency the adverse events reported during
clinical trials of 525 subjects with psoriasis.
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Table 3. Adverse Events Frequently Reported during Clinical Trials
Percent of Subjects Reporting (N = 525)
Body System
>75%
50% to 75%
25% to 50%
10% to 25%
CNS
Rigors
Eye Disorders
Xerophthalmia
Mucous Membranes
Cheilitis
Rhinitis
Dry mouth
Epistaxis
Musculoskeletal
Arthralgia
Spinal hyperostosis
(progression of
existing lesions)
Skin and Appendages
Alopecia
Skin peeling
Dry skin
Nail disorder
Pruritus
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Table 4. Adverse Events Less Frequently Reported during Clinical Trials (Some of Which
May Bear No Relationship to Therapy)
Percent of Subjects Reporting (N = 525)
Body System
1% to 10%
<1%
Body as a Whole
Anorexia
Edema
Fatigue
Hot flashes
Increased appetite
Alcohol
intolerance
Dizziness
Fever
Influenza-like
Malaise
Moniliasis
Muscle weakness
Weight increase
symptoms
Cardiovascular
Flushing
Chest pain
Cyanosis
Increased
bleeding time
Intermittent
claudication
Peripheral
ischemia
CNS (also see
Psychiatric)
Headache
Pain
Abnormal gait
Migraine
Neuritis
Pseudotumor
cerebri
(intracranial
hypertension)
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Eye Disorders
Abnormal/
blurred vision
Blepharitis
Conjunctivitis/
irritation
Corneal epithelial
abnormality
Decreased night
vision/night
blindness
Eye abnormality
Eye pain
Photophobia
Abnormal
lacrimation
Chalazion
Conjunctival
hemorrhage
Corneal ulceration
Diplopia
Ectropion
Itchy eyes and lids
Papilledema
Recurrent sties
Subepithelial
corneal lesions
Gastrointestinal
Abdominal pain
Diarrhea
Nausea
Tongue disorder
Constipation
Dyspepsia
Esophagitis
Gastritis
Gastroenteritis
Glossitis
Hemorrhoids
Melena
Tenesmus
Tongue ulceration
Liver and Biliary
Hepatic function
abnormal
Hepatitis
Jaundice
Mucous Membranes Gingival bleeding
Gingivitis
Increased saliva
Stomatitis
Thirst
Ulcerative
stomatitis
Altered saliva
Anal disorder
Gum hyperplasia
Hemorrhage
Pharyngitis
Musculoskeletal
Arthritis
Arthrosis
Back pain
Hypertonia
Myalgia
Osteodynia
Peripheral joint
hyperostosis
(progression of
existing lesions)
Bone disorder
Olecranon bursitis
Spinal hyperostosis
(new lesions)
Tendonitis
Psychiatric
Depression
Insomnia
Somnolence
Anxiety
Dysphonia
Libido decreased
Nervousness
Reproductive
Atrophic vaginitis
Leukorrhea
Respiratory
Sinusitis
Coughing
Increased sputum
Laryngitis
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Skin and
Appendages
Abnormal skin
odor
Abnormal hair
texture
Bullous eruption
Cold/clammy skin
Dermatitis
Increased
sweating
Infection
Psoriasiform rash
Purpura
Pyogenic
granuloma
Rash
Seborrhea
Skin fissures
Skin ulceration
Sunburn
Acne
Breast pain
Cyst
Eczema
Fungal infection
Furunculosis
Hair discoloration
Herpes simplex
Hyperkeratosis
Hypertrichosis
Hypoesthesia
Impaired healing
Otitis media
Otitis externa
Photosensitivity
reaction
Psoriasis
aggravated
Scleroderma
Skin nodule
Skin hypertrophy
Skin disorder
Skin irritation
Sweat gland
disorder
Urticaria
Verrucae
Special Senses/
Other
Earache
Taste perversion
Tinnitus
Ceruminosis
Deafness
Taste loss
Urinary
Abnormal urine
Dysuria
Penis disorder
Laboratory: Therapy with SORIATANE induces changes in liver function tests in a
significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were
experienced by approximately 1 in 3 subjects treated with SORIATANE. In most subjects,
elevations were slight to moderate and returned to normal either during continuation of therapy
or after cessation of treatment. In subjects receiving SORIATANE during clinical trials, 66% and
33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density
lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient, usually reversible elevations
of alkaline phosphatase have been observed.
Table 5 lists the laboratory abnormalities reported during clinical trials.
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Table 5. Abnormal Laboratory Test Results Reported during Clinical Trials
Percent of Subjects Reporting
Body System
50% to 75%
25% to 50%
10% to 25%
1% to 10%
Electrolytes
Increased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Magnesium
Decreased:
–Phosphorus
–Potassium
–Sodium
Increased and
decreased:
–Calcium
–Chloride
Hematologic
Increased:
–Reticulocytes
Decreased:
–Hematocrit
–Hemoglobin
–WBC
Increased:
–Haptoglobin
–Neutrophils
–WBC
Increased:
–Bands
–Basophils
–Eosinophils
–Hematocrit
–Hemoglobin
–Lymphocytes
–Monocytes
Decreased:
–Haptoglobin
–Lymphocytes
–Neutrophils
–Reticulocytes
Increased or
decreased:
–Platelets
–RBC
Hepatic
Increased:
–Cholesterol
–LDH
–SGOT
–SGPT
Decreased:
–HDL cholesterol
Increased:
–Alkaline
phosphatase
–Direct bilirubin
–GGTP
Increased:
–Globulin
–Total bilirubin
–Total protein
Increased and
decreased:
–Serum albumin
Miscellaneous
Increased:
–Triglycerides
Increased:
–CPK
–Fasting blood
sugar
Decreased:
–Fasting blood
sugar
–High occult
blood
Increased and
decreased:
–Iron
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Renal
Increased:
–Uric acid
Increased:
–BUN
–Creatinine
Urinary
WBC in urine
Acetonuria
Hematuria
RBC in urine
Glycosuria
Proteinuria
OVERDOSAGE
In the event of acute overdosage, SORIATANE must be withdrawn at once. Symptoms of
overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral
toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg per kg.
In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25-mg
capsules (525-mg single dose). He vomited several hours later but experienced no other ill
effects.
All female patients of childbearing potential who have taken an overdose of SORIATANE
must:
1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed
CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth
defects and contraceptive use for at least 3 years’ duration after the overdose.
DOSAGE AND ADMINISTRATION
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side
effects with SORIATANE. A number of the more common side effects are dose-related.
Individualization of dosage is required to achieve sufficient therapeutic response while
minimizing side effects. Therapy with SORIATANE should be initiated at 25 to 50 mg per day,
given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be
given dependent upon an individual patient’s response to initial treatment. Relapses may be
treated as outlined for initial therapy.
When SORIATANE is used with phototherapy, the prescriber should decrease the
phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS:
General).
Females who have taken TEGISON (etretinate) must continue to follow the
contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the
US; for information, call Stiefel at 1-888-784-3335 (1-888-STIEFEL).
Information for Pharmacists: SORIATANE must only be dispensed in no more than a
monthly supply. A SORIATANE Medication Guide must be given to the patient each time
SORIATANE is dispensed, as required by law.
HOW SUPPLIED:
Brown and white capsules, 10 mg, imprinted “A-10 mg”; bottles of 30 (NDC 0145-0090-25).
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_____________________________________________________________
Rich yellow capsules, 17.5 mg, imprinted “A-17.5 mg”; bottles of 30 (NDC 0145-3817-03).
Brown and yellow capsules, 25 mg, imprinted “A-25 mg”; bottles of 30 (NDC 0145-0091
25).
Store between 15° and 25°C (59° and 77°F). Protect from light. Avoid exposure to high
temperatures and humidity after the bottle is opened.
REFERENCES:
1. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389.
2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after
long-term acitretin. Lancet 348:1107, 1996.
3. Geiger JM, Walker M: Is there a reproductive safety risk in male patients treated with acitretin
(Neotigason®/ Soriatane ®)? Dermatology 205:105-107, 2002.
4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica
175:48-49, 1987.
5. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670).
Andrologia 22:479-482, 1990.
6. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin. In:
Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3, pp
253-254, 1988.
PATIENT AGREEMENT/INFORMED CONSENT FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber avoid pregnancy logo
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each item.
Do not sign this consent and do not take SORIATANE® (acitretin) if there is anything that
you do not understand.
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects
if I am pregnant or become pregnant while taking SORIATANE in any amount even for short
periods of time. Birth defects have also happened in babies of women who became pregnant after
stopping treatment with SORIATANE.
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INITIAL: ___________
2. I understand that I must not become pregnant while taking SORIATANE and for at least 3
years after the end of my treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter
products that contain alcohol. I understand that the risk of birth defects may last longer than 3
years if I swallow any form of alcohol during therapy with SORIATANE, and for 2 months after
I stop taking SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective forms
of birth control at the same time. The only exceptions are if I have had surgery to remove the
womb (a hysterectomy) or my prescriber has told me I have gone completely through
menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at the same
time for at least 1 month before starting SORIATANE, for the entire time of therapy with
SORIATANE, and for at least 3 years after stopping SORIATANE.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different methods
at the same time, every time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary:
Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills (not
progestin-only “minipills”), injectable/implantable/insertable/topical (patch) hormonal
birth control products, and IUDs (intrauterine devices). Secondary: Condoms (with or
without spermicide, which is a special cream or jelly that kills sperm), diaphragms and
cervical caps (which must be used with a spermicide), and vaginal sponges (contains
spermicide). I understand that at least 1 of my 2 methods of birth control must be a
primary method.
INITIAL: ___________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to take while
taking SORIATANE because certain birth control methods may not work if I am taking certain
medicines or herbal products (for example, St. John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely through
menopause, I understand that I must have 2 negative pregnancy test results before I can get a
prescription to start SORIATANE. I understand that if the second pregnancy test is negative, I
must start taking my SORIATANE within 7 days of the specimen collection. I will then have
pregnancy tests on a monthly basis during therapy with SORIATANE as instructed by my
prescriber. In addition, for at least 3 years after I stop taking SORIATANE, I will have a
pregnancy test every 3 months.
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_______________________________________________________________
_______________________________________________________________
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not
pregnant and have negative results from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraception (birth control)
counseling session and pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during therapy with SORIATANE and every 3 months
for at least 3 years after stopping SORIATANE that I should receive counseling from my
prescriber about contraception (birth control) and behaviors associated with an increased risk of
pregnancy.
INITIAL: ___________
14. I understand that I must stop taking SORIATANE right away and call my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without
using my 2 birth control methods during and at least 3 years after stopping SORIATANE.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of stopping
SORIATANE, I understand that I should report my pregnancy to Stiefel at 1-888-784-3335 (1
888-STIEFEL) or to the Food and Drug Administration (FDA) MedWatch program at 1-800
FDA-1088. The information I share will be kept confidential (private) unless disclosure is legally
required. This will help the company and the FDA evaluate the pregnancy prevention program to
prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T.™ brochure. My prescriber has answered
all my questions about SORIATANE. I understand that it is my responsibility to follow my
doctor’s instructions, and not to get pregnant during treatment with SORIATANE or for
at least 3 years after I stop taking SORIATANE.
I now authorize my prescriber,
______________________________________________________, to begin my treatment with
SORIATANE.
Patient signature: ________________________________________
Date: ___________________
Parent/guardian signature (if under age 18): ____________________
Date: ___________________
Please print: Patient name and address:
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Telephone: _____________________________________________________________
I have fully explained to the patient,
_________________________________________________, the nature and purpose of the
treatment described above and the risks to females of childbearing potential. I have asked the
patient if she has any questions regarding her treatment with SORIATANE and have answered
those questions to the best of my ability.
Prescriber signature: _______________________________________
Date: __________________
Revised 05/2015
SRN:XPI
MEDICATION GUIDE
SORIATANE® (sor-RYE-uh-tane)
(acitretin)
Capsules
Read this Medication Guide carefully before you start taking SORIATANE and read it
each time you get more SORIATANE. There may be new information.
The first information in this Guide is about birth defects and how to avoid
pregnancy. After this section there is important safety information about
possible effects for any patient taking SORIATANE. ALL patients should read
this entire Medication Guide carefully.
This information does not take the place of talking with your prescriber about your
medical condition or treatment.
What is the most important information I should know about SORIATANE?
SORIATANE can cause serious side effects, including:
1. Severe birth defects. If you are a female who can get pregnant, you should
use SORIATANE only if you are not pregnant now, can avoid becoming pregnant for
at least 3 years, and other medicines do not work for your severe psoriasis or you
cannot use other psoriasis medicines. Information about effects on unborn babies
and about how to avoid pregnancy is found in the next section: “What are the
important warnings and instructions for females taking SORIATANE?”
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avoid pregnancy logo
2. Liver problems, including abnormal liver function tests and inflammation of
your liver (hepatitis). Your prescriber should do blood tests to check how your liver
is working before you start taking and during treatment with SORIATANE. Stop
taking SORIATANE and call your prescriber right away if you have any of the
following signs or symptoms of a serious liver problem:
• yellowing of your skin or the whites of your eyes
• nausea and vomiting
• loss of appetite
• dark urine
What are the important warnings and instructions for females taking
SORIATANE?
• Before you receive your first prescription for SORIATANE, you should
have discussed and signed a Patient Agreement/Informed Consent for
Female Patients form with your prescriber. This is to help make sure
you understand the risk of birth defects and how to avoid getting
pregnant. If you did not talk to your prescriber about this and sign the
form, contact your prescriber.
NOTE: If you are a female who can become pregnant:
• You must not take SORIATANE if you are pregnant or might become
pregnant during treatment or at any time for at least 3 years after you
stop treatment because SORIATANE can cause severe birth defects.
• During treatment with SORIATANE and for 2 months after you stop
treatment with SORIATANE, you must avoid drinks, foods, and all
medicines that contain alcohol. This includes over-the-counter products
that contain alcohol. Avoiding alcohol is very important, because alcohol
changes SORIATANE into a drug that may take longer than 3 years to leave your
body. The chance of birth defects may last longer than 3 years if you swallow
any form of alcohol during treatment with SORIATANE and for 2 months after
you stop taking SORIATANE.
• You and your prescriber must be sure you are not pregnant before you
start therapy with SORIATANE. You must have negative results from 2
pregnancy tests before you start treatment with SORIATANE. A negative
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result shows you are not pregnant. Because it takes a few days after pregnancy
begins for a test to show that you are pregnant, the first negative test may not
ensure you are not pregnant. Do not start SORIATANE until you have negative
results from 2 pregnancy tests.
• The first pregnancy test (urine or blood) will be done at the time you and
your prescriber decide if SORIATANE might be right for you.
• The second pregnancy test will usually be done during the first 5 days of
your menstrual period. You must start taking SORIATANE within 7 days of
when the urine or blood for the second pregnancy test is collected.
• After you start taking SORIATANE, you must have a pregnancy test repeated
each month that you are taking SORIATANE. This is to be sure that you are not
pregnant during treatment because SORIATANE can cause birth defects. In
addition, your prescription of SORIATANE will be limited to a monthly supply.
• For at least 3 years after stopping treatment with SORIATANE, you must have a
pregnancy test repeated every 3 months to make sure that you are not
pregnant.
• Discuss effective birth control (contraception) with your prescriber. You
must use 2 effective forms of birth control (contraception) at the same
time during all of the following:
o for at least 1 month before beginning treatment with SORIATANE
o during treatment with SORIATANE
o for at least 3 years after stopping treatment with SORIATANE
• If you are sexually active, you must use 2 effective forms of birth
control (contraception) at the same time even if you think you cannot
become pregnant, unless 1 of the following is true for you:
o You had your womb (uterus) removed during an operation (a
hysterectomy).
o Your prescriber said you have gone completely through menopause
(the “change of life”).
• You can get a free birth control counseling session and pregnancy
testing from a prescriber or family planning expert. Your prescriber can
give you a Contraception Counseling Referral Form for this free session.
The following are considered effective forms of birth control:
Primary Forms:
• having your tubes tied (tubal ligation)
• partner’s vasectomy
• IUD (Intrauterine device)
• birth control pills that contain both estrogen and progestin (combination oral
contraceptives); not progestin-only “minipills”
• hormonal birth control products that are injected, implanted, or inserted in
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your body
• birth control patch
Secondary Forms (use with a Primary Form):
• diaphragms with spermicide
• condoms (with or without spermicide)
• cervical caps with spermicide
• vaginal sponge (contains spermicide)
At least 1 of your 2 methods of birth control must be a primary form.
• If you have sex at any time without using 2 effective forms of birth
control (contraception) at the same time, or if you get pregnant or miss
your period, stop using SORIATANE and call your prescriber right away.
• Consider “Emergency Contraception” (EC) if you have sex with a male
without correctly using 2 effective forms of birth control
(contraception) at the same time. EC is also called “emergency birth control”
or the “morning after” pill. Contact your prescriber as soon as possible if you
have sex without using 2 effective forms of birth control (contraception) at the
same time, because EC works best if it is used within 1 or 2 days after sex. EC is
not a replacement for your usual 2 effective forms of birth control
(contraception) because it is not as effective as regular birth control methods.
You can get EC from private doctors or nurse practitioners, women’s health
centers, or hospital emergency rooms. You can get the name and phone number
of EC providers nearest you by calling the free Emergency Contraception Hotline
at 1-888-668-2528 (1-888-NOT-2-LATE).
• Stop taking SORIATANE right away and contact your prescriber if you
get pregnant while taking SORIATANE or at any time for at least 3 years
after treatment has stopped. You need to discuss the possible effects on
the unborn baby with your prescriber.
• If you do become pregnant while taking SORIATANE or at any time for
at least 3 years after stopping SORIATANE, you should report your
pregnancy to Stiefel Laboratories, Inc. at 1-888-784-3335 (1-888
STIEFEL) or directly to the Food and Drug Administration (FDA)
MedWatch program at 1-800-FDA-1088. Your name will be kept in private
(confidential). The information you share will help the FDA and the manufacturer
evaluate the Pregnancy Prevention Program for SORIATANE.
• Do not take SORIATANE if you are breastfeeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
What should males know before taking SORIATANE?
Small amounts of SORIATANE are found in the semen of males taking SORIATANE.
Based upon available information, it appears that these small amounts of
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SORIATANE in semen pose little, if any, risk to an unborn child while a male patient
is taking the drug or after it is discontinued. Discuss any concerns you have about
this with your prescriber.
All patients should read the rest of this Medication Guide.
What is SORIATANE?
SORIATANE is a medicine used to treat severe forms of psoriasis in adults. Psoriasis
is a skin disease that causes cells in the outer layer of the skin to grow faster than
normal and pile up on the skin’s surface. In the most common type of psoriasis, the
skin becomes inflamed and produces red, thickened areas, often with silvery scales.
Because SORIATANE can have serious side effects, you should talk with your
prescriber about whether possible benefits of SORIATANE outweigh its possible
risks.
SORIATANE may not work right away. You may have to wait 2 to 3 months before
you get the full benefit of SORIATANE. Psoriasis gets worse for some patients when
they first start treatment with SORIATANE.
SORIATANE has not been studied in children.
Who should not take SORIATANE?
• Do NOT take SORIATANE if you can get pregnant. Do not take SORIATANE
if you are pregnant or might get pregnant during treatment with SORIATANE or
at any time for at least 3 years after you stop treatment with SORIATANE (see
“What are the important warnings and instructions for females taking
SORIATANE?”).
• Do NOT take SORIATANE if you are breastfeeding. SORIATANE can pass
into your milk and may harm your baby. You will need to choose either to breast
feed or take SORIATANE, but not both.
• Do NOT take SORIATANE if you have severe liver or kidney disease.
• Do NOT take SORIATANE if you have repeated high blood lipids (fat in
the blood).
• Do NOT take SORIATANE if you take these medicines:
o methotrexate
o tetracyclines
The use of these medicines with SORIATANE may cause serious side effects.
• Do NOT take SORIATANE if you are allergic to acitretin, the active
ingredient in SORIATANE, to any of the other ingredients in SORIATANE (see the
end of this Medication Guide for a list of all the ingredients in SORIATANE), or to
any medicines that are like SORIATANE. Ask your prescriber or pharmacist if any
medicines you are allergic to are like SORIATANE.
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Tell your prescriber if you have or ever had:
• diabetes or high blood sugar
• liver problems
• kidney problems
• high cholesterol or high triglycerides (fat in the blood)
• heart disease
• depression
• alcoholism
• an allergic reaction to a medication
Your prescriber needs this information to decide if SORIATANE is right for you and
to know what dose is best for you.
Tell your prescriber about all the medicines you take, including prescription
and over-the-counter medicines, vitamins, and herbal supplements. Some
medicines can cause serious side effects if taken while you also take SORIATANE.
Some medicines may affect how SORIATANE works, or SORIATANE may affect how
your other medicines work. Be especially sure to tell your prescriber if you are
taking the following medicines:
• methotrexate
• tetracyclines
• glyburide
• phenytoin
• vitamin A supplements
• progestin-only oral contraceptives (“minipills”)
• TEGISON® or TIGASON (etretinate). Tell your prescriber if you have ever taken
this medicine in the past.
• St. John’s wort herbal supplement
Tell your prescriber if you are getting phototherapy treatment. Your doses of
phototherapy may need to be changed to prevent a burn.
How should I take SORIATANE?
• Take SORIATANE with food.
• Be sure to take your medicine as prescribed by your prescriber. The dose of
SORIATANE varies from patient to patient. The number of capsules you must
take is chosen specially for you by your prescriber. This dose may change during
treatment.
• If you miss a dose, do not double the next dose. Skip the missed dose and
resume your normal schedule.
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• If you take too much SORIATANE (overdose), call your local poison control
center or emergency room.
You should have blood tests for liver function, cholesterol, and triglycerides before
starting treatment and during treatment to check your body’s response to
SORIATANE. Your prescriber may also do other tests.
Once you stop taking SORIATANE, your psoriasis may return. Do not treat this new
psoriasis with leftover SORIATANE. It is important to see your prescriber again for
treatment recommendations because your situation may have changed.
What should I avoid while taking SORIATANE?
• Avoid pregnancy. See “What is the most important information I should know
about SORIATANE?”, and “What are the important warnings and instructions for
females taking SORIATANE?”
• Avoid breastfeeding. See “What are the important warnings and instructions
for females taking SORIATANE?”
• Avoid alcohol. Females who are able to become pregnant must avoid drinks,
foods, medicines, and over-the-counter products that contain alcohol. The risk
of birth defects may continue for longer than 3 years if you swallow any form of
alcohol during treatment with SORIATANE and for 2 months after stopping
SORIATANE (see “What are the important warnings and instructions for females
taking SORIATANE?”).
• Avoid giving blood. Do not donate blood while you are taking SORIATANE
and for at least 3 years after stopping treatment with SORIATANE.
SORIATANE in your blood can harm an unborn baby if your blood is given to a
pregnant woman. SORIATANE does not affect your ability to receive a blood
transfusion.
• Avoid progestin-only birth control pills (“minipills”). This type of birth
control pill may not work while you take SORIATANE. Ask your prescriber if you
are not sure what type of pills you are using.
• Avoid night driving if you develop any sudden vision problems. Stop
taking SORIATANE and call your prescriber if this occurs (see “Serious side
effects”).
• Avoid non-medical ultraviolet (UV) light. SORIATANE can make your skin
more sensitive to UV light. Do not use sunlamps, and avoid sunlight as much as
possible. If you are taking light treatment (phototherapy), your prescriber may
need to change your light dosages to avoid burns.
• Avoid dietary supplements containing vitamin A. SORIATANE is related to
vitamin A. Therefore, do not take supplements containing vitamin A, because
they may add to the unwanted effects of SORIATANE. Check with your
prescriber or pharmacist if you have any questions about vitamin supplements.
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• DO NOT SHARE SORIATANE with anyone else, even if they have the
same symptoms. Your medicine may harm them or their unborn child.
What are the possible side effects of SORIATANE?
SORIATANE can cause serious side effects. See “What is the most important
information I should know about SORIATANE?” and “What are the
important warnings and instructions for females taking SORIATANE?”
Stop taking SORIATANE and call your prescriber right away if you get the
following signs or symptoms of possible serious side effects:
• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be
signs of increased brain pressure that can lead to blindness or even death.
• Vision problems. Decreased vision in the dark (night blindness). Since
this can start suddenly, you should be very careful when driving at night. This
problem usually goes away when treatment with SORIATANE stops. Stop taking
SORIATANE and call your prescriber if you develop any vision problems or eye
pain.
• Depression. There have been some reports of patients developing mental
problems including a depressed mood, aggressive feelings, or thoughts of
ending their own life (suicide). These events, including suicidal behavior, have
been reported in patients taking other drugs similar to SORIATANE as well as
patients taking SORIATANE. Since other things may have contributed to these
problems, it is not known if they are related to SORIATANE.
• Aches or pains in your bones, joints, muscles, or back, trouble moving,
or loss of feeling in your hands or feet. These can be signs of abnormal
changes to your bones or muscles.
• Frequent urination, great thirst or hunger. SORIATANE can affect blood
sugar control, even if you do not already have diabetes. These are some of the
signs of high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble
speaking, or swelling of a leg. These may be signs of a heart attack,
blood clots, or stroke. SORIATANE can cause serious changes in blood fats
(lipids). It is possible for these changes to cause blood vessel blockages that
lead to heart attacks, strokes, or blood clots.
• Blood vessel problems. SORIATANE can cause fluid to leak out of your blood
vessels into your body tissues. Call your prescriber right away if you have
any of the following symptoms: sudden swelling in one part of your body or
all over your body, weight gain, fever, lightheadedness or feeling faint, or
muscle aches. If this happens, your prescriber will tell you to stop taking
SORIATANE.
• Serious allergic reactions. See “Who should not take SORIATANE?” Serious
allergic reactions can happen during treatment with SORIATANE. Call your
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prescriber right away if you get any of the following symptoms of an
allergic reaction: hives, itching, swelling of your face, mouth, or tongue, or
problems breathing. If this happens, stop taking SORIATANE and do not
take it again.
• Serious skin problems. SORIATANE can cause skin problems that can begin in
a small area and then spread over large areas of your body. Call your
prescriber right away if your skin becomes red and swollen (inflamed),
you have peeling of your skin, or your skin becomes itchy and painful.
You should stop SORIATANE if this happens.
Common side effects
If you develop any of these side effects or any unusual reaction, check with your
prescriber to find out if you need to change the amount of SORIATANE you take.
These side effects usually get better if the dose of SORIATANE is reduced or
SORIATANE is stopped.
• Chapped lips, peeling fingertips, palms, and soles, itching, scaly skin all
over, weak nails, sticky or fragile (weak) skin, runny or dry nose, or
nosebleeds. Your prescriber or pharmacist can recommend a lotion or cream to
help treat drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
• Hair loss. Most patients have some hair loss, but this condition varies among
patients. No one can tell if you will lose hair, how much hair you may lose or if
and when it may grow back. You may also lose your eyelashes.
• Dry eyes. SORIATANE may dry your eyes. Wearing contact lenses may be
uncomfortable during and after treatment with SORIATANE because of the dry
feeling in your eyes. If this happens, remove your contact lenses and call your
prescriber. Also read the section about vision under “Serious side effects”.
• Rise in blood fats (lipids). SORIATANE can cause your blood fats (lipids) to
rise. Most of the time this is not serious. But sometimes the increase can
become a serious problem (see information under “Serious side effects”). You
should have blood tests as directed by your prescriber.
Psoriasis gets worse for some patients when they first start treatment with
SORIATANE. Some patients have more redness or itching. If this happens, tell your
prescriber. These symptoms usually get better as treatment continues, but your
prescriber may need to change the amount of your medicine.
These are not all the possible side effects of SORIATANE. For more information, ask
your prescriber or pharmacist.
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Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store SORIATANE?
•
Keep SORIATANE away from sunlight, high temperature, and humidity.
•
Keep SORIATANE and all medicines out of the reach of children.
What are the ingredients in SORIATANE?
Active ingredient: acitretin.
Inactive ingredients: black monogramming ink, gelatin, maltodextrin (a mixture of
polysaccharides), microcrystalline cellulose, and sodium ascorbate. Gelatin capsule
shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide.
They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate
calcium disodium.
General information about the safe and effective use of SORIATANE
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use SORIATANE for a condition for which it was not
prescribed. Do not give SORIATANE to other people, even if they have the same
symptoms that you have.
This Medication Guide summarizes the most important information about
SORIATANE. If you would like more information, talk with your prescriber. You can
ask your pharmacist or prescriber for information about SORIATANE that is written
for health professionals.
For more information about SORIATANE call 1-888-784-3335 or go to
www.soriatane.com.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Manufactured for company logo
Stiefel Laboratories, Inc.
Research Triangle Park, NC 27709
Revised 05/2015
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TEGISON® is a registered trademark of Hoffmann-La Roche Inc.
Do Your P.A.R.T. is a trademark and SORIATANE is a registered trademark of
Stiefel Laboratories, Inc.
©2015, Stiefel Laboratories, Inc.
SRN:XMG
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____________________________________
________________
____________________________________
____________________________________
________________________
AUTHORIZATION FOR USE OR DISCLOSURE OF HEALTH INFORMATION
I authorize the use or disclosure of health information about me as described below.
1. I agree to permit my doctor and Stiefel Laboratories, Inc., its affiliates, and those
working with Stiefel Laboratories or its affiliates (Stiefel) to use and disclose health
information about me.
2. I agree to permit Stiefel to receive the following health information about me: All
health information related to reimbursement of certain costs related to lab work and
physician counseling, and health information in my medical records that is relevant to
my treatment with SORIATANE® (acitretin).
3. Stiefel is authorized to use the information to determine if I qualify for
reimbursement under the Do Your P.A.R.T.TM program and, if it is determined that I
qualify, in providing my doctor reimbursement for certain approved costs.
4. I understand that Stiefel is not a health care provider or health plan covered by federal
privacy regulations, and when the information described above is disclosed to Stiefel
it will no longer be protected by these regulations.
5. I understand that I may refuse to sign this authorization. If I do not sign, however, I
understand that I will not be able to apply for or receive reimbursement of certain
costs under the Do Your P.A.R.T.™ program.
6. I understand that I may revoke this authorization at any time by sending a written
request to Stiefel Laboratories, Inc., Attn: Do Your P.A.R.T.™, 5150 McCrimmon
Parkway, Morrisville, NC 27560 , except to the extent that action has been taken in
reliance on this authorization.
7. This authorization expires 1 year after my participation in the Do Your P.A.R.T.™
program ends.
Signature of patient or representative
Date
Patient name
Name of personal representative (if applicable)
Relationship to patient
(A copy of this signed form will be provided to the patient.)
Patient Copy company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
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____________________________________
________________
____________________________________
____________________________________
________________________
AUTHORIZATION FOR USE OR DISCLOSURE OF HEALTH INFORMATION
I authorize the use or disclosure of health information about me as described below.
1. I agree to permit my doctor and Stiefel Laboratories, Inc., its affiliates, and those
working with Stiefel Laboratories or its affiliates (Stiefel) to use and disclose health
information about me.
2. I agree to permit Stiefel to receive the following health information about me: All
health information related to reimbursement of certain costs related to lab work and
physician counseling, and health information in my medical records that is relevant to
my treatment with SORIATANE® (acitretin).
3. Stiefel is authorized to use the information to determine if I qualify for
reimbursement under the Do Your P.A.R.T.TM program and, if it is determined that I
qualify, in providing my doctor reimbursement for certain approved costs.
4. I understand that Stiefel is not a health care provider or health plan covered by federal
privacy regulations, and when the information described above is disclosed to Stiefel
it will no longer be protected by these regulations.
5. I understand that I may refuse to sign this authorization. If I do not sign, however, I
understand that I will not be able to apply for or receive reimbursement of certain
costs under the Do Your P.A.R.T.™ program.
6. I understand that I may revoke this authorization at any time by sending a written
request to Stiefel Laboratories, Inc., Attn: Do Your P.A.R.T.™., 5150 McCrimmon
Parkway, Morrisville, NC 27560, except to the extent that action has been taken in
reliance on this authorization.
7. This authorization expires 1 year after my participation in the Do Your P.A.R.T.™
program ends.
Signature of patient or representative
Date
Patient name
Name of personal representative (if applicable)
Relationship to patient
(A copy of this signed form will be provided to the patient.)
Stiefel Copy company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
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CONTRACEPTION COUNSELING REFERRAL FORM (SORIATANE®) avoid pregnancy logo
Notes to Contraception Counselor
This patient, ____________________, is being considered for treatment with
SORIATANE® (acitretin). She has been referred to you for contraception counseling
before she receives a prescription for SORIATANE.
SORIATANE is a potent teratogen; therefore, it is essential to rule out pregnancy before
her treatment begins and for you to fully inform the patient about effective contraception.
The typical course of therapy with SORIATANE may last several months, depending
upon the patient’s response to the medication. The patient must choose 2 effective forms
of contraception to be used simultaneously for at least 1 month prior to initiation of
therapy with SORIATANE, during therapy with SORIATANE, and for at least 3 years
after discontinuing therapy with SORIATANE. According to the package insert for
SORIATANE, the following are considered effective forms of contraception:
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices,
injectable/implantable/insertable hormonal birth control products, and birth control patch.
Birth control pills that contain both estrogen and progestin (combination oral
contraceptives) are considered an effective form of birth control; however, progestin-only
(“minipills”) birth control pills should be avoided.
Secondary: Condoms (with or without spermicide), diaphragms and cervical caps (which
must be used with a spermicide), and vaginal sponges (contain spermicide).
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive
failure, and the requirements for achieving maximal effectiveness with her chosen
methods. Please inform me if the patient does not choose 2 effective forms of
contraception. The patient should also be counseled about emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2
pregnancy tests with a sensitivity of at least 25 mIU per mL. The first test should be done
at the time the patient decides to pursue therapy. The second test should be done during
the first 5 days of the menstrual period immediately preceding the beginning of therapy
with SORIATANE; or, if the patient has amenorrhea, the pregnancy test should be done
at least 11 days after the last act of unprotected sexual intercourse (without using 2
Reference ID: 3759716
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effective forms of contraception simultaneously). If the second pregnancy test is
negative, initiation of treatment with SORIATANE should begin within 7 days of the
specimen collection. SORIATANE should be limited to a monthly supply.
Prescriber’s name: ____________________________________________
(Please affix label, or type or print clearly.)
Address: ________________________________________________________________
Telephone: ______________________________________________________________
Prescriber’s signature: ____________________
Date: _____________
Information to Be Returned to Prescriber
I have provided the following for your patient _______________________________
(Name)
Comprehensive contraception counseling
Information about emergency contraception
The patient had a negative pregnancy test on _______________________________
(Date)
The patient has chosen 2 methods of contraception.
Yes
No
Primary method: ____________________________________________________
Secondary method: __________________________________________________
Name: ____________________________________________________________
(Please affix label, or type or print clearly.)
Address: __________________________________________________________
Telephone: ________________________________________________________
Contraception counselor’s signature: __________________ Date: ____________
Contraception Counselor Copy company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
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Reimbursement
NOTE: Reimbursement is offered only for contraception counseling and pregnancy
testing, if performed. Other services that may be provided during this visit are not eligible
for reimbursement.
The prescriber who actually prescribes SORIATANE® (acitretin) is not eligible for
reimbursement by Stiefel® .
REIMBURSEMENT INSTRUCTIONS
To receive reimbursement, you must call a toll-free number for reimbursement. After you
have provided all the requested information, a check will be sent to you by first-class
mail.
Steps: Dial 1-888-784-3335 (1-888-STIEFEL).
• You will be asked to provide the following information:
-
Your name and address
-
Your office phone number
-
Name of graduate school from which you graduated
-
Year of graduation
-
The name and address of the referring prescriber
-
The patient’s name
-
Whether you have provided contraception counseling and information on
emergency contraception
-
Your normal and customary charge for providing these services
• A check will then be processed and mailed to you within 10 days.
• To check on the status of a previous request, you will need to provide only your
name, address, and phone number. A representative will contact you to update
your request status.
REIMBURSEMENT FOR PREGNANCY TEST
If you have performed pregnancy testing in the office or sent the patient directly to the
laboratory, please instruct the laboratory to send the bill to the following address:
Stiefel Laboratories, Inc.
Attn: Director, Global Clinical Safety and Pharmacovigilance
20 T.W. Alexander Drive
Research Triangle Park, NC 27709
Important: Your name and address must be included on the invoice from the laboratory.
The laboratory will be reimbursed directly.
Reference ID: 3759716
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NOTE TO CONSULTANTS: By participating in this program, you agree to provide Stiefel with access to additional information
should it become necessary to confirm the appropriateness of this request for reimbursement. Stiefel reserves the right to place
limitations on reimbursements or deny reimbursements in certain situations. company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRACEPTION COUNSELING REFERRAL FORM (SORIATANE®) avoid pregnancy logo
Notes to Contraception Counselor
This patient, ____________________, is being considered for treatment with
SORIATANE® (acitretin). She has been referred to you for contraception counseling
before she receives a prescription for SORIATANE.
SORIATANE is a potent teratogen; therefore, it is essential to rule out pregnancy before
her treatment begins and for you to fully inform the patient about effective contraception.
The typical course of therapy with SORIATANE may last several months, depending
upon the patient’s response to the medication. The patient must choose 2 effective forms
of contraception to be used simultaneously for at least 1 month prior to initiation of
therapy with SORIATANE, during therapy with SORIATANE, and for at least 3 years
after discontinuing therapy with SORIATANE. According to the package insert for
SORIATANE, the following are considered effective forms of contraception:
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices,
injectable/implantable/insertable hormonal birth control products, and birth control patch.
Birth control pills that contain both estrogen and progestin (combination oral
contraceptives) are considered an effective form of birth control; however, progestin-only
(“minipills”) birth control pills should be avoided.
Secondary: Condoms (with or without spermicide), diaphragms and cervical caps (which
must be used with a spermicide), and vaginal sponges (contain spermicide).
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive
failure, and the requirements for achieving maximal effectiveness with her chosen
methods. Please inform me if the patient does not choose 2 effective forms of
contraception. The patient should also be counseled about emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2
pregnancy tests with a sensitivity of at least 25 mIU per mL. The first test should be done
at the time the patient decides to pursue therapy. The second test should be done during
the first 5 days of the menstrual period immediately preceding the beginning of therapy
with SORIATANE; or, if the patient has amenorrhea, the pregnancy test should be done
at least 11 days after the last act of unprotected sexual intercourse (without using 2
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
effective forms of contraception simultaneously). If the second pregnancy test is
negative, initiation of treatment with SORIATANE should begin within 7 days of the
specimen collection. SORIATANE should be limited to a monthly supply.
Prescriber’s name: ____________________________________________
(Please affix label, or type or print clearly.)
Address: ________________________________________________________________
Telephone: ______________________________________________________________
Prescriber’s signature: ____________________
Date: _____________
Information to Be Returned to Prescriber
I have provided the following for your patient _______________________________
(Name)
Comprehensive contraception counseling
Information about emergency contraception
The patient had a negative pregnancy test on _______________________________
(Date)
The patient has chosen 2 methods of contraception.
Yes
No
Primary method: ____________________________________________________
Secondary method: __________________________________________________
Name: ____________________________________________________________
(Please affix label, or type or print clearly.)
Address: __________________________________________________________
Telephone: ________________________________________________________
Contraception counselor’s signature: __________________ Date: ____________
Prescriber Copy company logo
©2015 Stiefel Laboratories, Inc. All rights
reserved. Printed in USA. SRN:XX## Rev May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reimbursement
NOTE: Reimbursement is offered only for contraception counseling and pregnancy
testing, if performed. Other services that may be provided during this visit are not eligible
for reimbursement.
The prescriber who actually prescribes SORIATANE® (acitretin) is not eligible for
reimbursement by Stiefel® .
REIMBURSEMENT INSTRUCTIONS
To receive reimbursement, you must call a toll-free number for reimbursement. After you
have provided all the requested information, a check will be sent to you by first-class
mail.
Steps: Dial 1-888-784-3335 (1-888-STIEFEL).
• You will be asked to provide the following information:
-
Your name and address
-
Your office phone number
-
Name of graduate school from which you graduated
-
Year of graduation
-
The name and address of the referring prescriber
-
The patient’s name
-
Whether you have provided contraception counseling and information on
emergency contraception
-
Your normal and customary charge for providing these services
• A check will then be processed and mailed to you within 10 days.
• To check on the status of a previous request, you will need to provide only your
name, address, and phone number. A representative will contact you to update
your request status.
REIMBURSEMENT FOR PREGNANCY TEST
If you have performed pregnancy testing in the office or sent the patient directly to the
laboratory, please instruct the laboratory to send the bill to the following address:
Stiefel Laboratories, Inc.
Attn: Director, Global Clinical Safety and Pharmacovigilance
20 T.W. Alexander Drive
Research Triangle Park, NC 27709
Important: Your name and address must be included on the invoice from the laboratory.
The laboratory will be reimbursed directly.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE TO CONSULTANTS: By participating in this program, you agree to provide Stiefel with access to additional information
should it become necessary to confirm the appropriateness of this request for reimbursement. Stiefel reserves the right to place
limitations on reimbursements or deny reimbursements in certain situations. avoid pregnancy logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRACEPTION COUNSELING REFERRAL FORM (SORIATANE®) avoid pregnancy logo
Notes to Contraception Counselor
This patient, ____________________, is being considered for treatment with
SORIATANE® (acitretin). She has been referred to you for contraception counseling
before she receives a prescription for SORIATANE.
SORIATANE is a potent teratogen; therefore, it is essential to rule out pregnancy before
her treatment begins and for you to fully inform the patient about effective contraception.
The typical course of therapy with SORIATANE may last several months, depending
upon the patient’s response to the medication. The patient must choose 2 effective forms
of contraception to be used simultaneously for at least 1 month prior to initiation of
therapy with SORIATANE, during therapy with SORIATANE, and for at least 3 years
after discontinuing therapy with SORIATANE. According to the package insert for
SORIATANE, the following are considered effective forms of contraception:
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices,
injectable/implantable/insertable hormonal birth control products, and birth control patch.
Birth control pills that contain both estrogen and progestin (combination oral
contraceptives) are considered an effective form of birth control; however, progestin-only
(“minipills”) birth control pills should be avoided.
Secondary: Condoms (with or without spermicide), diaphragms and cervical caps (which
must be used with a spermicide), and vaginal sponges (contain spermicide).
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive
failure, and the requirements for achieving maximal effectiveness with her chosen
methods. Please inform me if the patient does not choose 2 effective forms of
contraception. The patient should also be counseled about emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2
pregnancy tests with a sensitivity of at least 25 mIU per mL. The first test should be done
at the time the patient decides to pursue therapy. The second test should be done during
the first 5 days of the menstrual period immediately preceding the beginning of therapy
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
c
ompany logo
with SORIATANE; or, if the patient has amenorrhea, the pregnancy test should be done
at least 11 days after the last act of unprotected sexual intercourse (without using 2
effective forms of contraception simultaneously). If the second pregnancy test is
negative, initiation of treatment with SORIATANE should begin within 7 days of the
specimen collection. SORIATANE should be limited to a monthly supply.
Prescriber’s name: ____________________________________________
(Please affix label, or type or print clearly.)
Address: ________________________________________________________________
Telephone: ______________________________________________________________
Prescriber’s signature: ____________________
Date: _____________
Information to Be Returned to Prescriber
I have provided the following for your patient _______________________________
(Name)
Comprehensive contraception counseling
Information about emergency contraception
The patient had a negative pregnancy test on _______________________________
(Date)
The patient has chosen 2 methods of contraception.
Yes
No
Primary method: ____________________________________________________
Secondary method: __________________________________________________
Name: ____________________________________________________________
(Please affix label, or type or print clearly.)
Address: __________________________________________________________
Telephone: ________________________________________________________
Contraception counselor’s signature: __________________ Date: ____________
Return This Copy to Prescriber
©2015 Stiefel Laboratories, Inc. All rights
reserved. Printed in USA. SRN:XX## May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reimbursement
NOTE: Reimbursement is offered only for contraception counseling and pregnancy
testing, if performed. Other services that may be provided during this visit are not eligible
for reimbursement.
The prescriber who actually prescribes SORIATANE® (acitretin) is not eligible for
reimbursement by Stiefel® .
REIMBURSEMENT INSTRUCTIONS
To receive reimbursement, you must call a toll-free number for reimbursement. After you
have provided all the requested information, a check will be sent to you by first-class
mail.
Steps: Dial 1-888-784-3335 (1-888-STIEFEL).
• You will be asked to provide the following information:
-
Your name and address
-
Your office phone number
-
Name of graduate school from which you graduated
-
Year of graduation
-
The name and address of the referring prescriber
-
The patient’s name
-
Whether you have provided contraception counseling and information on
emergency contraception
-
Your normal and customary charge for providing these services
• A check will then be processed and mailed to you within 10 days.
• To check on the status of a previous request, you will need to provide only your
name, address, and phone number. A representative will contact you to update
your request status.
REIMBURSEMENT FOR PREGNANCY TEST
If you have performed pregnancy testing in the office or sent the patient directly to the
laboratory, please instruct the laboratory to send the bill to the following address:
Stiefel Laboratories, Inc.
Attn: Director, Global Clinical Safety and Pharmacovigilance
20 T.W. Alexander Drive
Research Triangle Park, NC 27709
Important: Your name and address must be included on the invoice from the laboratory.
The laboratory will be reimbursed directly.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE TO CONSULTANTS: By participating in this program, you agree to provide Stiefel with access to additional information
should it become necessary to confirm the appropriateness of this request for reimbursement. Stiefel reserves the right to place
limitations on reimbursements or deny reimbursements in certain situations. company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRACEPTION COUNSELING REFERRAL PROGRAM
Expert Counseling With No Added Expenses avoid pregnancy logo
Before you can start taking SORIATANE® (acitretin), you have to be sure that you are
not pregnant and that you understand how to avoid pregnancy. That’s why Stiefel
Laboratories, Inc. will pay for you to go to a contraception counselor. This specialist will
provide you with expert counseling about birth control (contraception and avoiding
pregnancy). This counseling is very important, even if you already feel you know about
birth control, and even if you are not having sex or do not plan to have sex.
6 Simple Instructions
1
Make an appointment to see a contraception counselor and give him/her the attached
forms. The counselor should call your prescriber if there are any questions about why you
are there or about how the program works.
2
Notify your prescriber after you have had contraception counseling.
3
Ask the contraception counselor to mail a copy of the form to your prescriber. You will
not get your first prescription for SORIATANE until your prescriber has received
this signed form, and you must have negative results from 2 pregnancy tests. Your
first test will be done at the time you and your prescriber decide if SORIATANE might
be right for you. The second pregnancy test will usually be done during the first 5 days of
your menstrual period right before you plan to start SORIATANE. If the second
pregnancy test is negative, initiation of treatment with SORIATANE should begin within
7 days of the specimen collection. SORIATANE should be limited to a monthly supply.
4
You must use 2 effective forms of birth control (contraception) at the same time for at
least 1 month before beginning treatment with SORIATANE, during treatment with
SORIATANE, and for at least 3 years after you stop taking SORIATANE.
5
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
You are not required to pay any charges for the counseling by the contraception
counselor. If you are asked to pay, have your contraception counselor send your signed
Authorization for Use or Disclosure of Health Information form to the address below.
The counselor should follow the instructions on the attached forms. The fee will be paid
by Stiefel Laboratories, Inc.
6
Finally, if your contraception counselor performs a pregnancy test, the laboratory bill
should be sent to the following address:
Stiefel Laboratories, Inc.
Attn: Director, Global Clinical Safety and Pharmacovigilance
20 T.W. Alexander Drive
Research Triangle Park, NC 27709
Patient Copy company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev
May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
COVER
HEAD:
SERIOUS TREATMENT
SERIOUS DECISIONS
COPY:
DO YOUR P.A.R.T.TM
Pregnancy Prevention Actively Required During & After Treatment
SIG: avoid pregnancy logo
new SORIATANE logo
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FIRST INSIDE SPREAD/LEFT
HEAD:
TABLE OF CONTENTS
PAGES
COPY:
Introduction
1
General Information
2-3
Avoiding Pregnancy
4-5
Additional Considerations
6
Birth Control Methods
7-12
Patient Self-Evaluation
13-14
Your Personal Record
15
Notes/Personal Contact Information
16
Patient Agreement/Informed Consent for Female Patients Form Back Pocket
Contraception Counseling Referral Program Form
Back Pocket
Medication Guide for Patients
Back Pocket
Patient Privacy Form (HIPAA Authorization Form)
Back Pocket
BOXED WARNING: avoid pregnancy logo
CONTRAINDICATIONS AND WARNINGS: SORIATANE® (acitretin) must not be used
by females who are pregnant or who may become pregnant during therapy or at any
time for at least 3 years after discontinuation of treatment. SORIATANE also must
not be used by females of reproductive potential who may not use 2 effective forms
of contraception (birth control) simultaneously for at least 1 month before, during,
and for at least 3 years after treatment. Two effective forms of contraception (birth
control) are to be used simultaneously, even when 1 form is a hormonal
contraceptive. Patients should not self-medicate with St. John’s wort because of a
possible interaction with hormonal contraceptives. Prescribers must obtain negative
results for 2 pregnancy tests before initiating treatment with SORIATANE. The first
test is a screening test; the second is a confirmation test done during the first 5 days
of the menstrual period immediately preceding therapy with SORIATANE. For
patients with amenorrhea, the second test should be done at least 11 days after the
last act of unprotected sexual intercourse. If the second pregnancy test is negative,
initiation of treatment with SORIATANE should begin within 7 days of the specimen
collection. SORIATANE should be limited to a monthly supply. Pregnancy testing
throughout the treatment course should be monthly. Females must sign a Patient
Agreement/Informed Consent for Female Patients form about the risks of birth
defects. Acitretin is a metabolite of etretinate and major fetal abnormalities have
been reported with both drugs. Acitretin can interact with ethanol to form etretinate.
Therefore, females of reproductive potential must not ingest ethanol during
treatment and for 2 months after cessation of treatment. Before prescribing, please
see complete pregnancy warning in the accompanying complete prescribing
information. Females who have undergone treatment with TEGISON® (etretinate)
must continue to follow the contraception requirements for TEGISON.
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FAIR BALANCE:
Less frequent, but potentially serious, adverse events include hepatotoxicity,
pancreatitis, and pseudotumor cerebri (please see WARNINGS in complete
prescribing information), as well as hyperostosis, alterations in lipids, possible
cardiovascular effects, ophthalmologic effects, capillary leak syndrome, and
exfoliative dermatitis/erythrodema.
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FIRST INSIDE SPREAD/RIGHT [PAGE 1]
HEAD:
INTRODUCTION
COPY:
ABOUT SORIATANE
SORIATANE® (acitretin) is a medicine used to treat severe forms of psoriasis in
adults. Psoriasis is a skin disease that causes cells in the outer layer of the skin to
grow faster than normal and pile up on the skin’s surface. In the most common type
of psoriasis, the skin becomes inflamed and produces red, thickened areas, often
with silvery scales. Because SORIATANE can have serious side effects, you
should talk with your prescriber about whether the possible benefits of SORIATANE
outweigh its possible risks.
In women of childbearing potential, SORIATANE should be reserved for non-pregnant
patients who are unresponsive to other therapies or whose clinical condition
contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND
WARNINGS — SORIATANE can cause severe birth defects).
Most patients experience relapse of psoriasis after stopping therapy. Subsequent
courses, when clinically indicated, have produced efficacy results similar to the initial
course of therapy.
ABOUT THE DO YOUR P.A.R.T.™ PROGRAM
This program applies to you because your doctor has prescribed SORIATANE for you.
This program is for women of childbearing potential.
SORIATANE can cause severe birth defects during treatment and for up to 3 years
after a patient stops SORIATANE. The Do Your P.A.R.T.™ program is intended to
help you avoid getting pregnant during this time.
The SORIATANE Do Your P.A.R.T.™ Program contains several important
components:
This booklet
Patient Agreement/Informed Consent for Female Patients form
Contraception Counseling Referral Program form (optional)
A Medication Guide for Patients
Authorization for Use or Disclosure of Health Information
Voluntary Patient Survey
Patient Survey Brochure
Patient Survey Registration Form
Read and complete all of these materials before taking SORIATANE, and be sure to
ask your doctor about any questions you have.
YOUR SEXUAL PARTNER
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
It is strongly recommended that your sexual partner read this booklet in order to
understand all of the facts about the risks of birth defects for women taking
SORIATANE. It is critical that you and your sexual partner know that you must not
become pregnant during or within 3 years after you stop using SORIATANE.
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SECOND INSIDE SPREAD/LEFT [PAGE 2]
HEAD:
GENERAL INFORMATION
COPY:
WHAT IS SORIATANE?
SORIATANE is a medicine used to treat severe forms of psoriasis in adults. Psoriasis
is a skin disease that causes cells in the outer layer of the skin to grow faster than
normal, creating a “traffic jam” of skin cells on the surface. The skin becomes red,
irritated, inflamed, thicker, and sometimes has a silvery appearance.
Because SORIATANE can have serious side effects, you should talk with your doctor
to see if it is right for you.
SORIATANE might not work right away. It might take 2 or 3 months before your skin
may begin to improve.
Psoriasis gets worse for some patients when they first start taking SORIATANE.
SORIATANE has not been studied in children.
Please see the enclosed Medication Guide for Patients for additional information
about SORIATANE.
You may also ask your doctor to provide you with the complete prescribing
information (package insert) for SORIATANE® (acitretin).
WHAT SHOULD I AVOID WHILE TAKING SORIATANE?
Do not get pregnant during therapy and for 3 years after treatment
discontinuation (SORIATANE can cause birth defects).
Do not breastfeed.
Do not consume alcohol (women of reproductive potential only).
Do not donate blood during therapy and for 3 years after treatment
discontinuation. Other women who could get pregnant must not receive blood
from patients being treated with SORIATANE.
Do not share SORIATANE with anyone, even if they have the same
symptoms.
Avoid night driving if you develop any sudden vision problems.
Avoid nonmedical ultraviolet (UV) light.
Avoid dietary supplements containing vitamin A.
Avoid progestin-only birth control pills (“minipills”).
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WHAT ARE THE POSSIBLE SIDE EFFECTS OF SORIATANE?
SORIATANE can cause birth defects. Refer to the enclosed Medication Guide for
Patients and see “What is the most important information I should know about
SORIATANE?” and “What are the important warnings and instructions for females
taking SORIATANE?”
Psoriasis gets worse for some patients when they first start treatment with
SORIATANE. Some patients have more redness or itching. If this happens, tell your
prescriber. These symptoms usually get better as treatment continues, but your
prescriber may need to change the amount of your medicine.
Serious side effects. These do not happen often, but they can lead to permanent
harm, or rarely, to death. Stop taking SORIATANE and call your prescriber right
away if you get the following signs or symptoms:
• Yellowing of your skin or the whites of your eyes, nausea and vomiting,
loss of appetite, or dark urine. These can be signs of serious liver damage.
• Bad headaches, nausea, vomiting, blurred vision. These symptoms can be
signs of increased brain pressure that can lead to blindness or even death.
• Vision Problems. Decreased vision in the dark (night blindness). Since this
can start suddenly, you should be very careful when driving at night. This problem
usually goes away when treatment with SORIATANE stops. Stop taking SORIATANE
and call your prescriber if you develop any vision problems or eye pain.
• Depression. There have been some reports of patients developing mental
problems including a depressed mood, aggressive feelings, or thoughts of ending
their own life (suicide). These events, including suicidal behavior, have been
reported in patients taking other drugs similar to SORIATANE as well as patients
taking SORIATANE. Since other things may have contributed to these problems, it
is not known if they are related to SORIATANE..
• Aches or pains in your bones, joints, muscles, or back, trouble moving, or
loss of feeling in your hands or feet. These can be signs of abnormal changes
to your bones or muscles.
• Frequent urination, great thirst or hunger. SORIATANE can affect blood sugar
control, even if you do not already have diabetes. These are some of the signs of
high blood sugar.
• Shortness of breath, dizziness, nausea, chest pain, weakness, trouble
speaking, or swelling of a leg. These may be signs of a heart attack, blood
clots, or stroke. SORIATANE can cause serious changes in blood fats (lipids). It is
possible for these changes to cause blood vessel blockages that lead to heart
attacks, strokes, or blood clots.
• Blood vessel problems. SORIATANE can cause fluid to leak out of your blood
vessels into your body tissues. Call your prescriber right away if you have
any of the following symptoms: sudden swelling in one part of your body or
Reference ID: 3759716
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all over your body, weight gain, fever, lightheadedness or feeling faint, or muscle
aches. If this happens your prescriber will tell you to stop taking SORIATANE.
• Serious allergic reactions. See “Who should not take SORIATANE?” in the
Medication Guide. Serious allergic reactions can happen during treatment with
SORIATANE. Call your prescriber right away if you get any of the following
symptoms of an allergic reaction: hives, itching, swelling of your face, mouth,
or tongue, or problems breathing. If this happens, stop taking SORIATANE
and do not take it again.
• Serious skin problems. SORIATANE can cause skin problems that can begin in
a small area and then spread over large areas of your body. Call your
prescriber right away if your skin becomes red and swollen (inflamed),
you have peeling of your skin, or your skin becomes itchy, and painful.
You should stop SORIATANE if this happens.
Common side effects. If you develop any of these side effects or any unusual
reaction, check with your prescriber to find out if you need to change the amount of
SORIATANEyou take. These side effects usually get better if the dose of SORIATANE
is reduced or SORIATANE is stopped.
• Chapped lips, peeling fingertips, palms, and soles, itching, scaly skin all
over, weak nails, sticky or fragile (weak) skin, runny or dry nose, or
nosebleeds. Your prescriber or pharmacist can recommend a lotion or cream to
help treat drying or chapping.
• Dry mouth
• Joint pain
• Tight muscles
• Hair loss. Most patients have some hair loss, but this condition varies among
patients. No one can tell if you will lose hair, how much hair you may lose, or if and
when it may grow back. You may also lose your eyelashes.
• Dry eyes. SORIATANE may dry your eyes. Wearing contact lenses may be
uncomfortable during and after treatment with SORIATANE because of the dry
feeling in your eyes. If this happens, remove your contact lenses and call your
prescriber. Also read the section about vision under “Serious side effects”.
• Rise in blood fats (lipids). SORIATANE can cause your blood fats (lipids) to rise.
Most of the time, this is not serious. But sometimes the increase can become a
serious problem (see information under “Serious side effects”). You should have
blood tests as directed by your prescriber.
These are not all the possible side effects of SORIATANE. For more information, ask
your prescriber or pharmacist.
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SECOND INSIDE SPREAD/RIGHT [PAGE 3]
COPY:
SORIATANE CAN CAUSE SEVERE BIRTH DEFECTS.
If you are a woman who could possibly become pregnant, and you and your doctor
think that SORIATANE is right for you, there are very important things to understand
before starting SORIATANE.
1. You MUST NOT get pregnant while taking SORIATANE.
You MUST have 2 negative pregnancy tests before starting SORIATANE. You
MUST start treatment with SORIATANE within 7 days of the specimen
collection. You MUST have a pregnancy test each month before receiving the
next month’s prescription and every 3 months for 3 years after
discontinuation. You MUST use 2 forms of birth control starting 1 month
before treatment, the whole time you are treated with SORIATANE, and for 3
years after you stop taking SORIATANE.
2. If you stop taking SORIATANE, you MUST NOT get pregnant for at
least 3 years. Keeping track of this time interval is extremely
important.
3. You MUST NOT consume alcohol of any kind while taking SORIATANE,
or for 2 months after you’ve stopped SORIATANE.
4. You MUST NOT donate blood during therapy and for 3 years after
treatment discontinuation.
5. You MUST sign the Patient Agreement/Informed Consent for Female
Patients Form.
IF YOU CANNOT AGREE TO THESE REQUIREMENTS, SORIATANE IS NOT FOR
YOU.
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE SCHEDULE FOR PREGNANCY PREVENTION & SAFE PREGNANCY
PLANNING
1 MONTH
BEFORE
TREATMENT
BEFORE
TREATMENT
DURING
TREATMENT
WITH
SORIATANE
2 MONTHS
AFTER
TREATMENT
3 YEARS
AFTER
TREATMENT
2 FORMS
OF BIRTH
CONTROL
2 NEGATIVE
PREGNANCY
TESTS
ONGOING
PREGNANCY
TESTS
Each month before receiving prescription and every 3 months for 3 years
after stopping treatment
NO
ALCOHOL
NO BLOOD
DONATION
SIGN
INFORMED
CONSENT
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
THIRD INSIDE SPREAD/LEFT [PAGE 4]
HEAD:
AVOIDING PREGNANCY avoid pregnancy logo
COPY:
IMPORTANT INFORMATION FOR FEMALE PATIENTS
SORIATANE is a very powerful drug, and women must be very careful not to become
pregnant. If it is possible for you to become pregnant, and you and your doctor
agree on using SORIATANE, you must:
Before starting SORIATANE, take 2 pregnancy tests proving that you’re
not pregnant. The first negative test will start the process, and the second
negative test will confirm the results. (Your doctor will tell you when and
how to take the tests.) Initiation of treatment with SORIATANE should
begin within 7 days of the specimen collection and should be limited to a
monthly supply.
Use 2 forms of birth control at the same time, for at least 1 month before
and during your treatment with SORIATANE and for at least 3 years after
you stop treatment with SORIATANE. You and your doctor should choose
2 forms of birth control. At least one of the methods must be a primary
method.
PRIMARY: (you must choose at least 1 from this list)
Birth control pills (but not progestin-only “minipills”)
Birth control patch
Intrauterine device (IUD)
Injected, implanted, or inserted hormonal birth control products
Having your tubes tied
Partner’s vasectomy
SECONDARY: (you may choose 1 from this list to use with primary method)
Diaphragm with spermicide
Cervical cap with spermicide
Condom with or without spermicide
Vaginal sponge (contains spermicide)
Before you receive your first prescription for SORIATANE, you should have discussed
and signed a Patient Agreement/Informed Consent for Female Patients form with
your prescriber. This is to help make sure you understand the risk of birth defects
Reference ID: 3759716
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and how to avoid getting pregnant. If you did not talk to your prescriber about this
and sign the form, contact your prescriber.
CALL-OUT:
WHOM CAN I CONTACT FOR BIRTH CONTROL INFORMATION?
TOLL-FREE NUMBER: 1-800-739-6700
A 24-hour, toll-free, automated birth control counseling line has been set up for you
to use.
Remember, calling this number is completely confidential—you will never have to
give your name, and you cannot be identified.
A 24-hour, toll-free, automated line is available to all patients on SORIATANE. You
can also share this information and phone number with members of your family and
your partner.
If you need more information about birth control options, the following sites are
available on the Internet:
-
Association of Reproductive Health Professionals: www.arhp.org
-
Planned Parenthood: www.plannedparenthood.org
If you need more information about drugs and birth defects, the following sites are
available on the Internet:
-
Organization of Teratology Information Services: www.mothertobaby.org
-
Centers for Disease Control and Prevention: www.cdc.gov
If you feel you need to talk to an expert on contraception, a Contraception Counselor
can be provided for you free of charge. Please see the Contraception Counseling
Referral Form at the back of this booklet for more information.
THIRD INSIDE SPREAD/RIGHT [PAGE 5]
COPY:
COMMONLY ASKED QUESTIONS
How long do I need to use birth control?
You need to start using 2 forms of birth control at least 1 month before you begin
taking SORIATANE.
You need to use 2 forms of birth control during your entire treatment with
SORIATANE.
You need to continue to use 2 forms of birth control for 3 years after you stop
taking SORIATANE.
If you think you have had unprotected sex or you feel that your contraception has
failed while taking SORIATANE:
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your physician and the emergency contraception hotline at 1-888-668-2528
(1-888-NOT-2-LATE) immediately.
What is “emergency contraception”?
Emergency contraception is an option that can be used if you have had unprotected
sex or your birth control method failed while taking SORIATANE (or within 3 years
after you stop). “Unprotected” means using fewer than 2 types of birth control, or 1
of the forms you were using failed. Emergency contraception is commonly referred to
as the “morning-after pill”, and needs to be used as directed after having
unprotected sex.
If you think you’ve become pregnant while taking SORIATANE or within 3 years of
stopping:
Stop taking SORIATANE.
Call your doctor to tell him/her you might be pregnant.
Call Stiefel at 1-888-784-3335 (1-888-STIEFEL).
Or call FDA MedWatch at 1-800-328-1088 (1-800-FDA-1088).
CALL-OUT:
IMPORTANT INFORMATION FOR MALE PATIENTS
Very small amounts of SORIATANE are found in the semen of males taking the
medication (1/200,000 of a single 25 mg capsule). Based upon available information,
it appears that these small amounts of SORIATANE in semen pose little, if any, risk
to an unborn child. Discuss any concerns you may have about this with your doctor.
FOURTH INSIDE SPREAD/LEFT [PAGE 6]
ADDITIONAL CONSIDERATIONS
What about alcohol?
Alcohol can increase the length of time SORIATANE is stored in a woman’s body,
causing the risk of birth defects to last longer than 3 years. It is essential that
women of reproductive potential do not drink alcohol during treatment with
SORIATANE, or for 2 months after they stop treatment.
Alcohol is in more places than you think. Even small amounts found in cold medicine,
or alcohol used in cooking, can make the possibility of birth defects last MUCH
longer. Be very careful not to allow any kind of alcohol into your body.
If you have any questions about alcohol and SORIATANE, ask your doctor.
What about breastfeeding?
Do not take SORIATANE if you’re breastfeeding. SORIATANE can pass into your milk
and may harm your baby.
What about donating blood?
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No person (male or female) should donate blood while taking SORIATANE, or for at
least 3 years after stopping therapy. The SORIATANE in your blood, if given to a
pregnant woman, could harm her baby. SORIATANE does not affect your ability to
receive a blood transfusion.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FOURTH INSIDE SPREADS/RIGHT [PAGE 7]
HEAD:
BIRTH CONTROL METHODS
COPY:
The following descriptions have been supplied to give you an overview of how each
birth control method works in your body. For more information, please ask your
doctor, refer to the information included with the individual product, or use the
resources listed in the “WHOM CAN I CONTACT FOR BIRTH CONTROL
INFORMATION?” section on page 4.
CALL-OUT:
What about MINIPILLS?
Do not use “minipills,” which may not work while you take SORIATANE.
Ask your prescriber if you are not sure what type of pills you are using.
PRIMARY METHODS
You must choose at least 1 from the following methods.
BIRTH CONTROL PILLS1
“The Pill” contains hormones that prevent you from becoming pregnant. These
hormones prevent your ovaries from releasing eggs and may also keep sperm from
joining with an egg. The Pill is safe and effective for most women, and is taken once
daily. The Pill needs to be prescribed by a doctor.
Two kinds are available for most women: one has a combination of hormones, and
the other has only one hormone (“minipills”).
Do not use “minipills,” which may not work while you take SORIATANE. Ask your
prescriber if you are not sure what type of pills you are using.
Effectiveness: Fewer than 1 in 100 women will become pregnant each year with
perfect use. With typical use, 9 in 100 women will become pregnant each year.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FIFTH INSIDE SPREAD/LEFT [PAGE 8]
COPY:
BIRTH CONTROL PATCH1
The patch, available by prescription, sends hormones into your body through your
skin. These hormones help prevent your ovaries from releasing eggs and may also
keep sperm from joining with an egg. A new patch is placed on the skin once a week
for three weeks in a row, followed by a patch-free week.
Effectiveness: Fewer than 1 in 100 women will become pregnant each year with
perfect use. With typical use, 9 in 100 women will become pregnant each year.
INTRAUTERINE DEVICE1
The intrauterine device (IUD) is placed inside your uterus by a doctor and usually
either contains copper or releases hormones. Both kinds of IUDs prevent fertilization
by affecting movement of sperm so they can’t join with an egg.
Effectiveness: Fewer than 1 in 100 women will become pregnant each year if an
IUD is used.
FIFTH INSIDE SPREAD/RIGHT [PAGE 9]
COPY:
INJECTED, IMPLANTED, OR INSERTED HORMONAL BIRTH CONTROL1
There are several different kinds of hormonal birth control that can prevent
pregnancy.
Injected or implanted hormones: This form is given to you by your healthcare
provider at specific time intervals. These hormone shots or implants prevent your
ovaries from releasing eggs and may also keep sperm from joining with an egg.
Injected hormone effectiveness: Fewer than 1 in 100 women will get pregnant
each year with perfect use. With typical use, 6 in 100 women will get pregnant each
year.
Implanted hormone effectiveness: Fewer than 1 in 100 women will get pregnant
each year. It lasts up to 3 years.
Inserted hormones: This form is usually called the “vaginal ring,” and you insert it
into your vagina. It must be prescribed by your doctor. After being properly inserted,
it releases a continuous low dose of hormones into your body. These hormones
prevent your ovaries from releasing eggs and may also keep sperm from joining with
an egg. The ring remains in the vagina for 3 weeks, and then is removed for 1 week.
Effectiveness: Fewer than 1 in 100 women will become pregnant each year with
perfect use. With typical use, 9 in 100 women will become pregnant each year.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SIXTH INSIDE SPREAD/LEFT [PAGE 10]
COPY:
TUBAL LIGATION1 (“HAVING YOUR TUBES TIED”) OR YOUR PARTNER’S
VASECTOMY1
Sterilization of women and men requires operations and are meant to be permanent.
“Having your tubes tied” (or tubal ligation) is intended to block a woman’s fallopian
tubes, where sperm would join with an egg. There are different types of sterilization
incision methods and a non-incision method (Essure). The non-incision method,
Essure, takes about 3 months before it is effective. An x-ray should be performed by
your doctor to confirm if the fallopian tubes are fully blocked.
A vasectomy is an operation that permanently disconnects a man’s semen duct,
which carries sperm. Vasectomies do not work immediately, and it often takes up to
3 months before all the live sperm are gone. A semen analysis should be performed
to confirm if there are no more live sperm.
Tubal ligation effectiveness: Approximately 5 in 1,000 women will become
pregnant after having a tubal ligation performed with traditional incision methods.
Fewer than 3 in 1,000 women will become pregnant after having tubal ligation
performed with Essure.
Vasectomy effectiveness: 1 in 1,000 men will become fertile again after a
vasectomy has been performed.
CONTINUOUS ABSTINENCE1
Continuous abstinence is not having sex play with a partner at all.
Effectiveness: When used continuously, abstinence is 100% effective in preventing
pregnancy.
MEDICALLY CONFIRMED MENOPAUSE2
Menopause is the time at "midlife" when a woman has her last period. It
happens when the ovaries stop releasing eggs — usually a gradual process.
Sometimes it happens all at once. It is confirmed when a woman has missed her
period for 12 consecutive months (which can not be attributed to other causes).
Menopause also results in lower levels of estrogen and other hormones.
Induced menopause occurs if the ovaries are removed or damaged during surgery,
chemotherapy, or radiation therapy. In this case, menopause begins immediately.
Women reach menopause at different times. The timing is not related to age at
last pregnancy, age of menarche (first period), the birth control pill, breastfeeding,
class, fertility patterns, height, having been pregnant, or race.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The average age for menopause is 51. If menopause is reached naturally or
surgically before the age of 40, it is called early or premature menopause.
Estrogen levels drop very abruptly after induced menopause — when both ovaries
are removed surgically or damaged by radiation or chemotherapy.
Women in perimenopause (the period of gradual changes that lead into
menopause) have reduced fertility but they are not infertile. Although menstruation
may be sporadic, pregnancy can happen. That's why women need to consider birth
control during perimenopause.
Only your doctor can confirm that you have reached menopause and do not need to
pursue contraceptive options.
HYSTERECTOMY3
Hysterectomy is the removal of the uterus. It is major surgery and is not usually
used for sterilization. It is used to correct significant medical conditions.
Hysterectomy ends menstruation as well as the possibility of pregnancy.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SIXTH INSIDE SPREAD/RIGHT [PAGE 11]
SECONDARY METHODS
You may choose 1 from these options to use with a primary method. Spermicide
must be used with the diaphragm and cervical cap. Spermicide is available in a
variety of forms and contains a chemical that prevents sperm from joining with an
egg. Spermicide may cause irritation. Changing forms or brands may help.
Spermicide is not required with condoms or vaginal sponge.
DIAPHRAGM1
The diaphragm is a shallow latex cup that you insert into your vagina. You must
have a custom fitting from a healthcare professional to obtain a diaphragm.
The diaphragm must be used with spermicide, and must stay in place for 6 hours
after sex. If you have sex again or if you have sex more than 6 hours after you put
in the diaphragm, more spermicide needs to be inserted deep into your vagina.
The diaphragm should not be left in place longer than 24 hours.
Effectiveness: 6 in 100 women will become pregnant each year with perfect use.
With typical use, 12 in 100 women will become pregnant each year.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SEVENTH INSIDE SPREAD/LEFT [PAGE 12]
COPY:
CERVICAL CAP1
The cervical cap is very similar to the diaphragm, except that it is smaller and covers
only the cervix. You must have a custom fitting from a healthcare professional to
obtain a cervical cap.
The cervical cap must be used with spermicide. With each sexual act, check that the
cervical cap is still covering the cervix and insert more spermicide deep into your
vagina. The cervical cap must stay in place for 6 hours after sex and should not be
left in longer than 48 hours.
Effectiveness for women who have never been pregnant or given birth
vaginally: 14 in 100 women who use the cervical cap will become pregnant each
year.
Effectiveness for women who have given birth vaginally: 29 in 100 women
who use the cervical cap will become pregnant each year.
CONDOM1
Male condoms are made of latex or plastic and are worn on the penis during
intercourse. Condoms prevent pregnancy by preventing sperm from entering the
vagina. Condoms are non-prescription and available at drugstores, health centers, or
grocery stores.
Effectiveness: 2 in 100 women whose partners use condoms will become pregnant
each year with perfect use. With typical use, 18 in 100 women whose partners use
condoms will become pregnant each year.
VAGINAL SPONGE1
The vaginal sponge is made of plastic foam and contains spermicide. The vaginal
sponge should be inserted before intercourse deep into the vagina so that it covers
the cervix. The vaginal sponge continuously releases a spermicide and blocks sperm
from entering the uterus. The vaginal sponge can be inserted up to 24 hours before
intercourse and must stay in place for 6 hours after sex. It should not be left in place
longer than 30 hours.
Effectiveness for women who have never given birth: 9 in 100 women will
become pregnant each year with perfect use. With typical use, 12 in 100 women will
become pregnant each year.
Effectiveness for women who have previously given birth: 20 in 100 will
become pregnant each year with perfect use. With typical use, 24 in 100 will become
pregnant each year.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SEVENTH INSIDE SPREAD/RIGHT [PAGE 13]
HEAD:
PATIENT SELF-EVALUATION
COPY:
Now that you have read the Do Your P.A.R.T.™ brochure and talked with your
doctor about SORIATANE and its risks, please use this self-evaluation exercise to test
your understanding of some of the most important points.
Please choose the best answer for each of the following 7 questions.
1. Treatment with SORIATANE requires prevention of pregnancy because:
a. Severe psoriasis may get worse after pregnancy
b. SORIATANE can cause birth defects
c. Psoriasis is more likely in children of psoriasis patients
d. None of the above
2. Before starting treatment with SORIATANE, it is important to be certain I am not
pregnant. To be certain, I must:
a. Test my urine at home with 2 pregnancy test kits
b. Have my doctor order 2 pregnancy tests, 2 weeks apart
c. Have my doctor do a screening test for pregnancy when we decide to treat
me with SORIATANE, and then test for pregnancy again during the first 5
days of my period (or at least 11 days after the last time I had sex
without birth control) to confirm I am not pregnant
d. Not have sex for one month
3. I must start using 2 effective forms of birth control:
a. At least 1 month before starting SORIATANE
b. At the time I take the first dose of SORIATANE
c. After my period ends
d. Now
4. I must continue using 2 effective forms of birth control:
a. As long as I continue to take SORIATANE
b. For 1 year after I stop taking SORIATANE
c. For 3 years after I stop taking SORIATANE
d. Until menopause
5. True or False? (circle one) T
F
It is important to avoid alcohol while taking SORIATANE and for 2 months after
stopping SORIATANE because alcohol can change SORIATANE into another substance
that may also cause birth defects, and that lasts in the body for even longer than
SORIATANE.
6. True or False? (circle one) T
F
A female patient with severe psoriasis has used birth control pills for 7 years after
her last child was born and they have worked just fine. She still needs to add a
second method of birth control before starting treatment with SORIATANE.
7. True or False? (circle one) T
F
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoiding pregnancy during and after treatment with SORIATANE is equally the
responsibility of my doctor, my partner, and me.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EIGTH INSIDE SPREAD/LEFT [PAGE 14]
HEAD:
ANSWERS
COPY:
1. b
While a and c are both true, the reason pregnancy prevention is required is because
SORIATANE can cause birth defects which can be severe. SORIATANE stays in the body
for a long time, so you should not get pregnant for at least 3 years after stopping
treatment. If you think you may want to become pregnant in the near future, you should
NOT take SORIATANE.
2. c
When we talk about "2 negative pregnancy tests," we mean a screening test and then a
confirmation test during your period. Both tests must be negative BEFORE starting
SORIATANE. It is important to be sure you are not pregnant because SORIATANE could
harm your developing baby.
3. a
It is important to be sure you have made the right choice of birth control for you and are
comfortable using the 2 forms of birth control. If cooperation from your partner is
involved, as with condoms, you need to be certain you both understand and accept the
requirement to use condoms every time you have sex. Starting 1 month before
SORIATANE also helps ensure you are not pregnant. If you and your doctor have decided
SORIATANE is right for you, now is a good time to start using 2 forms of birth control, but
you must use them for at least 1 month before starting SORIATANE.
4. c
Because SORIATANE remains in your body for a long time after you stop taking the drug,
the risk of birth defects continues and you must not get pregnant for at least 3 years after
stopping SORIATANE.
5. TRUE
Even a small amount of alcohol can affect how the body handles SORIATANE.
6. TRUE
Every method of birth control can fail, including birth control pills. Because the risk of birth
defects with exposure to SORIATANE is so serious, 2 reliable methods are recommended.
7. FALSE
Only you can truly prevent pregnancy. While your doctor will give you information, refer
you to counseling, and encourage you to make the right decision, and your partner's
cooperation and support with birth control methods is essential, the success of pregnancy
prevention during and after treatment is your responsibility.
SCORING:
7 correct? Well done!
If you got any question wrong, please review the brochure again and make sure you
understand. Thank you!
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Please be sure to discuss any questions or concerns you may have with your doctor before
starting treatment with SORIATANE. Other treatment options should be used if you are
not willing or able to take seriously the responsibility for pregnancy prevention and
actively follow all recommendations.
EIGTH INSIDE SPREAD/RIGHT [PAGE 15]
YOUR PERSONAL RECORD
NAME:
You MUST have 2 negative pregnancy tests performed by your doctor that show
you are NOT pregnant before starting therapy with SORIATANE.
The first test will be at the time that you and your doctor decide that SORIATANE
might be right for you.
1 TEST DATE
TEST RESULT
The second test will usually be done during the first 5 days of your menstrual
period . If the second pregnancy test is negative, initiation of treatment with
SORIATANE should begin within 7 days of the specimen collection. SORIATANE
should be limited to a monthly supply.
2 START OF MENSTRUAL PERIOD
TEST DATE
TEST RESULT
DATE THERAPY WITH SORIATANE BEGAN
FOLLOW-UP APPOINTMENTS
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE THERAPY WITH SORIATANE STOPPED
FOLLOW-UP APPOINTMENTS
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
DATE
TIME
NINTH INSIDE SPREAD/LEFT [PAGE 16]
NOTES/PERSONAL CONTACT INFORMATION
PHYSICIAN NAME:
PHYSICIAN PHONE:
PHARMACY NAME:
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PHARMACY PHONE:
OTHER:
OTHER:
NINTH INSIDE SPREAD/RIGHT [POCKET]
HEAD:
IMPORTANT PHONE NUMBERS
COPY:
BIRTH CONTROL COUNSELING
1-800-739-6700
EMERGENCY CONTRACEPTION HOTLINE
1-888-668-2528 (1-888-NOT-2-LATE)
IF YOU BECOME PREGNANT
1-888-784-3335 (1-888-STIEFEL)
Or
1-800-332-1088 (1-800-FDA-1088)
BACK COVER
updated Soriatane logo avoid pregnancy logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX##
Rev May 2015
REFERENCES:
1. Planned Parenthood: Birth Control. Available at:
http://www.plannedparenthood.org/health-info/birth-control. Accessed
November 12, 2014.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. The North American Menopause Society: Menopause 101. Available at:
http://www.menopause.org/for-women/menopauseflashes/menopause-101
a-primer-for-the-perimenopausal. Accessed November 12, 2014.
3. MedlinePlus: Hysterectomy. Available at:
http://www.nlm.nih.gov/medlineplus/hysterectomy.html. Accessed
November 12, 2014.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________________
Last Name
First Name
Zip code
(of your home address)
___________________________________________________________________________
/
/
Soriatane® Do Your P.A.R.T.™ Enrollment Patient Survey
Please complete the following:
DIRECTIONS: Please read the questions carefully. It is possible that you will have to skip
some questions. That’s okay. Not all questions will need to be answered. Some questions
are specific to your current status for your therapy with SORIATANE (e.g., patients just
starting therapy with SORIATANE, patients on active therapy, or patients who have either
temporarily or permanently stopped therapy). The survey will instruct you on which
questions to answer.
1.
What is today’s date? Please enter:
[GO TO Next Question]
(Month)
(Day)
(Year)
2.
Did you receive a Medication Guide explaining the safe use of and risks associated with
SORIATANE? (Choose only one)
Yes, from my doctor’s office
Yes, from my pharmacy
Yes, from both my doctor’s office and my pharmacy
No
I don’t know / I don’t remember
3.
Did your doctor review the risks and benefits associated with SORIATANE with you?
(Choose only one)
Yes
No, but someone else from my doctor’s office did
No, no one discussed this with me
I don’t know / I don’t remember
4.
Did your doctor answer all of your questions about SORIATANE? (Choose only one)
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
/
/
Yes
No, but someone else from my doctor’s office did
No, no one answered my questions
I don’t know / I don’t remember
5.
Did you complete and sign the Patient Agreement/Informed Consent for Female Patients
form in the doctor’s office? (Choose only one)
Yes
No
I don’t know / I don’t remember
6.
Did you receive and read the contraception counseling referral form? (Choose only one)
Yes, I received and read it
Yes, I received but have not yet read it
No
I don’t know / I don’t remember
7.
Are you currently taking SORIATANE®? (Choose only one)
No [SKIP TO Question # 9]
Yes [GO TO Next Question]
8.
When did you start your current therapy with SORIATANE? (Enter approximate month
and year)
[SKIP TO Question # 12]
(Month)
(Year)
9.
Read the responses below and choose the best answer: (Choose only one)
I have not yet started therapy with [GO TO Question # 10]
SORIATANE
I have stopped taking SORIATANE
[SKIP TO Question # 11]
10. When do you plan to BEGIN taking SORIATANE? (Enter the approximate month and
year)
[SKIP TO Question # 13]
(Month)
(Year)
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
/
/
11. What date did you STOP taking SORIATANE? (Enter the approximate month and year)
[GO TO Next Question]
(Month)
(Year)
12. Were you pregnant when you BEGAN taking SORIATANE? (Choose only one)
No
Yes
Don’t know
13. Did you have two negative pregnancy tests before receiving your first prescription for
SORIATANE? (Choose only one)
No [GO TO Next Question]
Yes [GO TO Next Question]
I don’t know [GO TO Next Question]
I have not received my first prescription yet [SKIP TO Question # 20]
14. Where do you obtain your SORIATANE? (Check all that apply)
Pharmacy
Internet
Other (specify): ______________________________
15. Removing the womb (uterus) is sometimes medically necessary, and is called a
hysterectomy. Since you have been on SORIATANE have you had a hysterectomy?
(Choose only one.)
No
I don’t know
Yes (If Yes, enter the approximate month and year below)
(Month)
(Year)
16. Since you have been on SORIATANE have you had both ovaries surgically removed?
(Choose only one.)
No
I don’t know
Yes (If Yes, enter the approximate month and year below)
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
/
/
/
(Month)
(Year)
17. Since you have been on SORIATANE has your doctor told you that your ovaries stopped
working and that you are in menopause? (Choose only one.)
No
I don’t know
Yes (If Yes, enter the approximate month and year below)
(Month)
(Year)
18. Have you become pregnant since obtaining/taking your SORIATANE? (Choose only one)
No
I don’t know
Yes (If Yes, enter the approximate month and year of
the most recent pregnancy below)
(Month)
(Year)
19. Since beginning treatment with SORIATANE, how often would you say that you used two
effective and different forms of birth control (as described in the Do Your P.A.R.T.™
program) for each episode of sexual intercourse?
Never
Not very often
Sometimes
Often
Always
20. Are you currently using 2 effective and different forms of birth control at each episode of
sexual intercourse?
Yes
No
I Don’t Know
If Yes, please identify forms of birth control currently used (check all that apply):
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
pill
(spe
/
C
Birth control patch
Tubal ligation
Birth control pills (contains
Vasectomy
estrogen and progesterone)
Birth control progestin-only mini-
Condoms
Injected hormonal birth control
Diaphragm
Inserted hormonal birth control
Cervical Cap
Implanted hormonal birth control
Spermicide
Intrauterine Device (IUD)
Sponge
Abstinence
Natural family planning
Withdrawal
None
method
Other
Emergency contraception
cify):_______________________
21. How often are you given a pregnancy test? (Choose only one)
Once a month
Every other month
Once every three months
Once every six months
Once a year
Never
Don’t know
22. To the best of your knowledge, enter the approximate month and year of your last
pregnancy test that was performed.
(Month)
(Year)
heck here if you can’t remember
23. Are you pregnant now? (Choose only one)
No
Yes
Don’t know
INSTRUCTIONS: In this section, there are four statements that could be either True or
False. Test your knowledge by reading each statement and determine if it is true or false.
Choose only one answer for each statement.
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
erson (
years
would
24. Because of the risk of birth defects from SORIATANE, you need to start using two forms
of birth control at least 1 month before you begin taking SORIATANE, for your entire
treatment with SORIATANE, and for 3 years after you stop taking SORIATANE.
False
True
25. Alcohol (even small amounts contained in medicines or used in cooking) can increase the
length of time SORIATANE is stored in a woman’s body, causing the risk of birth defects
as long as 3 years after stopping SORIATANE.
False
True
26. Because of the risk of birth defects, it is important that women of reproductive potential do
not drink alcohol during treatment with SORIATANE, and for two months after they stop
treatment.
False
True
27. No p
male or female) should donate blood while taking SORIATANE and for at
least 3
after stopping therapy.
False
True
28.
How
you like to complete future surveys? (Choose only one)
Paper form (mailed)
Internet (web-based)
END OF SURVEY – THANK YOU!
Please return the survey to:
Soriatane® Do Your P.A.R.T.™ Survey
5150 McCrimmon Parkway
Morrisville, NC 27560
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev May
2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_____________________________________________________________
PATIENT AGREEMENT/INFORMED CONSENT
FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber avoid pregnancy logo
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each
item. Do not sign this consent and do not take SORIATANE® (acitretin) if there is
anything that you do not understand.
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth
defects if I am pregnant or become pregnant while taking SORIATANE in any amount
even for short periods of time. Birth defects have also happened in babies of women who
became pregnant after stopping treatment with SORIATANE.
INITIAL: ___________
2. I understand that I must not become pregnant while taking SORIATANE and for at least
3 years after the end of my treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter
products that contain alcohol. I understand that the risk of birth defects may last longer than 3 years
if I swallow any form of alcohol during therapy with SORIATANE, and for 2 months after I stop taking
SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective
forms of birth control at the same time. The only exceptions are if I have had surgery to
remove the womb (a hysterectomy) or my prescriber has told me I have gone completely
through menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at
the same time for at least 1 month before starting SORIATANE, for the entire time of
therapy with SORIATANE, and for at least 3 years after stopping SORIATANE.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different
methods at the same time, every time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary:
Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills (not progestin-only
“minipills”), injectable/implantable/insertable/topical (patch) hormonal birth control products, and
IUDs (intrauterine devices). Secondary: Condoms (with or without spermicide, which is a special
cream or jelly that kills sperm), diaphragms and cervical caps (which must be used with a
spermicide), and vaginal sponges (contain spermicide). I understand that at least 1 of my 2
methods of birth control must be a primary method.
INITIAL: ___________
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
________________________________________________________________________________
________________________________________________________________________________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to
take while taking SORIATANE because certain birth control methods may not
work if I am taking certain medicines or herbal products (for example, St. John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely through
menopause, I understand that I must have 2 negative pregnancy test results before I can
get a prescription to start SORIATANE. I understand that if the second pregnancy test is negative, I must
start taking my SORIATANE within 7 days of specimen collection. I will then have pregnancy tests on a
monthly basis during therapy with SORIATANE as instructed by my prescriber. In addition, for at least 3
years after I stop taking SORIATANE, I will have a pregnancy test every 3 months.
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not
pregnant and have negative results from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraception
(birth control) counseling session and pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during therapy with SORIATANE and every 3 months for at least 3
years after stopping SORIATANE that I should receive counseling from my prescriber about contraception
(birth control) and behaviors associated with an increased risk of pregnancy.
INITIAL: ___________
14. I understand that I must stop taking SORIATANE right away and call my prescriber if I
get pregnant, miss my menstrual period, stop using birth control, or have sexual
intercourse without using my 2 birth control methods during and at least 3 years after
stopping SORIATANE.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of stopping
SORIATANE, I understand that I should report my pregnancy to Stiefel at
1-888-784-3335 (1-888-STIEFEL) or to the Food and Drug Administration (FDA) MedWatch
program at 1-800-FDA-1088. The information I share will be kept confidential (private) unless disclosure is
legally required.
This will help the company and the FDA evaluate the pregnancy prevention program to
prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T.™ brochure. My prescriber has answered all my
questions about SORIATANE. I understand that it is my responsibility to follow my
doctor’s instructions, and not to get pregnant during treatment with SORIATANE or for at least 3
years after I stop taking SORIATANE.
I now authorize my prescriber, ______________________________________________________, to
begin my treatment with SORIATANE.
Patient signature: ________________________________________ Date: ___________________
Parent/guardian signature (if under age 18): ____________________ Date: ___________________
Please print: Patient name and address:
Telephone: ________________________________________________________________
I have fully explained to the patient, _________________________________________________, the
nature and purpose of the treatment described above and the risks to females of childbearing potential. I
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have asked the patient if she has any questions regarding her treatment with SORIATANE and have
answered those questions to the best of my ability.
Prescriber signature: _______________________________________ Date: __________________
[Patient Copy] company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_____________________________________________________________
PATIENT AGREEMENT/INFORMED CONSENT
FOR FEMALE PATIENTS
To be completed by the patient* and signed by her prescriber avoid pregnancy logo
*Must also be initialed by the parent or guardian of a minor patient (under age 18)
Read each item below and initial in the space provided to show that you understand each
item. Do not sign this consent and do not take SORIATANE® (acitretin) if there is
anything that you do not understand.
(Patient’s name)
1. I understand that there is a very high risk that my unborn baby could have severe birth
defects if I am pregnant or become pregnant while taking SORIATANE in any amount
even for short periods of time. Birth defects have also happened in babies of women who
became pregnant after stopping treatment with SORIATANE.
INITIAL: ___________
2. I understand that I must not become pregnant while taking SORIATANE and for at least
3 years after the end of my treatment with SORIATANE.
INITIAL: ___________
3. I know that I must avoid all alcohol, including drinks, food, medicines, and over-the
counter products that contain alcohol. I understand that the risk of birth defects may last
longer than 3 years if I swallow any form of alcohol during therapy with SORIATANE, and
for 2 months after I stop taking SORIATANE.
INITIAL: ___________
4. I understand that I must not have sexual intercourse, or I must use 2 separate, effective
forms of birth control at the same time. The only exceptions are if I have had surgery to
remove the womb (a hysterectomy) or my prescriber has told me I have gone completely
through menopause.
INITIAL: ___________
5. I understand that I have to use 2 effective forms of birth control (contraception) at
the same time for at least 1 month before starting SORIATANE, for the entire time of
therapy with SORIATANE, and for at least 3 years after stopping SORIATANE.
INITIAL: ___________
6. I understand that any form of birth control can fail. Therefore, I must use 2 different
methods at the same time, every time I have sexual intercourse.
INITIAL: ___________
7. I understand that the following are considered effective forms of birth control: Primary:
Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills (not
progestin-only”minipills”), injectable/implantable/insertable/topical (patch) hormonal birth
control products, and IUDs (intrauterine devices). Secondary: Condoms (with or without
spermicide, which is a special cream or jelly that kills sperm), diaphragms and cervical
caps (which must be used with a spermicide), and vaginal sponges (contain spermicide). I
understand that at least 1 of my 2 methods of birth control must be a primary method.
INITIAL: ___________
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________
_______________________________________________________________________
8. I will talk with my prescriber about any medicines or dietary supplements I plan to
take while taking SORIATANE because certain birth control methods may not work if I am
taking certain medicines or herbal products (for example, St. John’s wort).
INITIAL: ___________
9. Unless I have had a hysterectomy or my prescriber says I have gone completely
through menopause, I understand that I must have 2 negative pregnancy test results
before I can get a prescription to start SORIATANE. I understand that if the second
pregnancy test is negative, I must start taking my SORIATANE within 7 days of the
specimen collection. I will then have pregnancy tests on a monthly basis during therapy
with SORIATANE as instructed by my prescriber. In addition, for at least 3 years after I
stop taking SORIATANE, I will have a pregnancy test every 3 months.
INITIAL: ___________
10. I understand that I should not start taking SORIATANE until I am sure that I am not
pregnant and have negative results from 2 pregnancy tests.
INITIAL: ___________
11. I have received information on emergency contraception (birth control).
INITIAL: ___________
12. I understand that my prescriber can give me a referral for a free contraception (birth
control) counseling session and pregnancy testing.
INITIAL: ___________
13. I understand that on a monthly basis during therapy with SORIATANE and every 3
months for at least 3 years after stopping SORIATANE that I should receive counseling
from my prescriber about contraception (birth control) and behaviors associated with an
increased risk of pregnancy.
INITIAL: ___________
14. I understand that I must stop taking SORIATANE right away and call my prescriber if I
get pregnant, miss my menstrual period, stop using birth control, or have sexual
intercourse without using my 2 birth control methods during and at least 3 years after
stopping SORIATANE.
INITIAL: ___________
15. If I do become pregnant while on SORIATANE or at any time within 3 years of
stopping SORIATANE, I understand that I should report my pregnancy to Stiefel at
1-888-784-3335 (1-888-STIEFEL) or to the Food and Drug Administration (FDA)
MedWatch program at 1-800-FDA-1088. The information I share will be kept confidential
(private) unless disclosure is legally required. This will help the company and the FDA
evaluate the pregnancy prevention program to prevent birth defects.
INITIAL: ___________
I have received a copy of the Do Your P.A.R.T.™ brochure. My prescriber has
answered all my questions about SORIATANE. I understand that it is my
responsibility to follow my doctor’s instructions, and not to get pregnant during
treatment with SORIATANE or for at least 3 years after I stop taking SORIATANE.
I now authorize my prescriber,
______________________________________________________, to begin my
treatment with SORIATANE.
Patient signature: ________________________________Date:___________________
Parent/guardian signature (if under age 18): _____________________________
Date: ___________________
Please print: Patient name and address:
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
________________________________________________________________
Telephone:
I have fully explained to the patient,
_________________________________________________, the nature and purpose of
the treatment described above and the risks to females of childbearing potential. I have
asked the patient if she has any questions regarding her treatment with SORIATANE and
have answered those questions to the best of my ability.
Prescriber signature: _______________________________Date: _________________
[Prescriber Copy] company logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev May 2015
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Patient Brochure
Updated Submission Text
The SORIATANE Do Your P.A.R.T.™ Survey: Patient Brochure Copy
Tri-Fold Brochure Panel Reference:
Printed Side: Front
Panel 1: Inside Fold Panel
Panel 2: Back Panel
Panel 3: Front Panel
Printed Side: Back
Panel 4: Inside Left Panel
Panel 5: Inside Center
Panel
Panel 6: Inside Right Panel
Panel 1: Inside Fold Panel
[GRAPHIC: Woman of child bearing potential]
What is the SORIATANE® (acitretin) Do Your P.A.R.T.™ Patient Survey?
The SORIATANE Survey is a short, easy-to-answer questionnaire about your use of
SORIATANE, pregnancy prevention and your understanding of the risks associated with using
SORIATANE. The questions are very similar to the topics that you have already discussed with
your doctor or nurse.
The survey is voluntary, but all women who have the potential to become pregnant while taking
SORIATANE and for three years after they stop taking SORIATANE are being asked to
participate.
Page 1 of 4
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Patient Brochure
Updated Submission Text
Panel 2: Back Panel
For more information, visit the SORIATANE® (acitretin) Do Your P.A.R.T.™ website at
www.soriatane.com.
HELPFUL PHONE NUMBERS:
BIRTH CONTROL COUNSELING:
1-800-739-6700
EMERGENCY CONTRACEPTION HOTLINE:
LATE)
1-888-668-2528 (1-888-NOT-2
IF YOU BECOME PREGNANT OR HAVE A SIDE EFFECT
FROM TAKING SORIATANE:
[Soriatane Logo]
1-888-784-3335 (1-888-STIEFEL)
OR
1-800-332-1088 (1-800-FDA-1088) avoid pregnancy logo
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev May 2015
Panel 3: Front Panel
[GRAPHIC: Photograph of woman of child bearing potential]
The SORIATANE® (acitretin) Do Your P.A.R.T.™ Survey: A Patient’s Guide to Participation
Pregnancy Prevention Actively Required During & After Treatment
[GRAPHIC: Soriatane logo]
Panel 4: Inside Left Panel[Graphic: Woman of Child-bearing potential]
Why Should You Participate?
Your doctor has asked you to participate in the SORIATANE® (acitretin) Survey because you
are able to become pregnant and were prescribed SORIATANE.
Page 2 of 4
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Patient Brochure
Updated Submission Text
Your participation will be simple: you will periodically complete a short survey questionnaire
while you are taking SORIATANE and for three years after you stop.
Sharing this valuable information on the effectiveness of the SORIATANE Do Your P.A.R.T.™
Program will help other women safely use SORIATANE in the future.
[GRAPHIC: Survey timeline]
SORIATANE SCHEDULE FOR PREGNANCY PREVENTION & SAFE PREGNANCY
PLANNING
1 MONTH
BEFORE
DURING
2 MONTHS
3 YEARS
BEFORE
TREATMENT
TREATMENT
AFTER
AFTER
TREATMENT
WITH
SORIATANE
TREATMENT
TREATMENT
2 FORMS
OF BIRTH
CONTROL
→
2 NEGATIVE
PREGNANCY
TESTS
→
ONGOING
PREGNANCY
TESTS
Each month before receiving prescription and every 3 months for 3 years
after stopping treatment
DO YOUR
→
→
P.A.R.T.
A SURVEY
A SURVEY
SURVEY
EVERY THREE
MONTHS
EVERY SIX
MONTHS
NO
ALCOHOL
→
NO BLOOD
DONATION
→
SIGN
INFORMED
CONSENT
→
Page 3 of 4
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Patient Brochure
Updated Submission Text
Panel 5: Inside Center Panel
[Graphic Woman of Child-Bearing Potential]
Your Participation in the Survey
We will contact you each time the survey is to be completed – you won’t have to remember!
You will have the option of completing the survey on paper or via the internet at the
SORIATANE® (acitretin) Survey website. Completing the survey will only take a few minutes.
While you are taking SORIATANE, you will be asked to complete a brief survey once every
three months.
After you stop taking SORIATANE, you will be asked to complete the survey two times a year
for three years.
You will be paid for your time after you complete each survey.
[GRAPHIC: Participation timeline]
Panel 6: Inside Right Panel
[Graphic: Woman of Child-Bearing Potential]
Your Privacy
We understand the importance of your privacy. Your participation in the SORIATANE®
(acitretin) Survey is completely confidential. Only the researchers and those working with the
researchers managing the survey will know your identity. Your name and contact information
will not be shared with others, and the answers you provide will never be identified with you in
any presentation of the survey results.
How to Contact Us
If you have questions about the SORIATANE Do Your P.A.R.T.™ survey, please call 1-877
351-5495.
Please see the back of this brochure for phone numbers to report a side effect or pregnancy, or
for information about birth control or contraception.
Thank You
Thank you for participating in the SORIATANE Survey. The information you provide will help
ensure the safe use of SORIATANE now and in the future.
[GRAPHIC: Soriatane logo]
Page 4 of 4
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Registration Form
Updated Submission Text
[Graphic: Woman of Child-Bearing Potential]
SORIATANE® (acitretin) Do Your P.A.R.T.™ Patient Survey Registration
[SORIATANE logo]
Purpose of the Survey
The SORIATANE® Do Your P.A.R.T.™ (Pregnancy Prevention Actively Required During
and After Treatment) patient survey is a short, easy-to-answer questionnaire that gathers
information about how women who can get pregnant use SORIATANE, the importance of
pregnancy prevention and patient understanding of the risks associated with using
SORIATANE.
What to Expect
You will be asked to complete a survey when you register, every three months while you are
taking SORIATANE and then twice a year for three years after you stop taking SORIATANE.
We will remind you when a survey is ready for you to complete. Each survey will take only a few
minutes of your time. You will complete your first survey on paper, but have your choice of
completing future surveys on paper or via the Internet. If you choose “Internet” below and
provide your e-mail address, you will be sent an e-mail with instructions on how to complete
future surveys online.
Your Privacy
Your participation in the survey and any answers that you provide are completely confidential.
Only the researchers and those working with the researchers managing the survey will know
your identity. Your name and contact information will not be shared with others, and the
answers you provide will never be identified with you in any presentation of the survey results.
Payment
We appreciate your participation in the SORIATANE Do Your P.A.R.T.™ patient survey. To
compensate you for your time, we will send you a $50 American Express gift card for every
survey you complete. The gift card can be used for purchases wherever American Express is
accepted.
How to Register
Registration is simple. Just fill out the form below, and be sure to sign and date it. Then, place
it in the provided postage-paid envelope along with your completed survey and drop it in the
mail. Be sure to let us know how you would like to receive future surveys.
Participant Information (please print)
I agree to participate in the SORIATANE Do Your P.A.R.T.™ patient survey
Name
Last
First
Middle Initial
Address
Street
Apt # City
State Zip Code
Telephone
Best time to call:
am/pm
Doctor’s Name
Doctor’s Address
Street
City
State Zip Code
Page 1 of 2
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SORIATANE Do Your P.A.R.T. Survey Registration Form
Updated Submission Text
Most recent date that you began treatment with SORIATANE (MM/DD/YYYY)
Month Day
Year
Signature
Date
How would you like to complete future surveys?
Pa
Int
per Form
ernet
Your E-mail Address
Misplaced your envelope? Send your form and your survey to:
SORIATANE Capsules Do Your P.A.R.T™ Survey
5150 McCrimmon Parkway
Morrisville, NC 27560
877-351-5495
©2015 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SRN:XX## Rev May 2015
Page 2 of 2
Reference ID: 3759716
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:01.055684
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019821s027lbl.pdf', 'application_number': 19821, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
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|
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
JOEL SCHIFFENBAUER
01/07/2013
Reference ID: 3241011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:01.076618
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019822Orig1s007lbl.pdf', 'application_number': 19822, 'submission_type': 'SUPPL ', 'submission_number': 7}
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2
LOPROX® Lotion
(ciclopirox)
0.77%
FOR DERMATOLOGIC USE ONLY.
NOT FOR USE IN EYES.
Rx Only
DESCRIPTION
LOPROX® Lotion (ciclopirox) 0.77% is for topical use.
Each gram of LOPROX® Lotion contains 7.70 mg of ciclopirox (as
ciclopirox olamine) in a water miscible lotion base consisting of Purified
Water USP, Cocamide DEA, Octyldodecanol NF, Mineral Oil USP,
Stearyl Alcohol NF, Cetyl Alcohol NF, Polysorbate 60 NF, Myristyl
Alcohol NF, Sorbitan Monostearate NF, Lactic Acid USP, and Benzyl
Alcohol NF (1%) as preservative.
LOPROX® Lotion contains a synthetic, broad-spectrum, antifungal agent
ciclopirox (as ciclopirox olamine). The chemical name is 6-cyclohexyl-1
-hydroxy-4-methyl-2(1H)-
pyridone, 2-aminoethanol salt.
The CAS Registry Number is 41621-49-2.
The chemical structure is:
LOPROX® Lotion has a pH of 7.
CLINICAL PHARMACOLOGY
Ciclopirox is a broad-spectrum, antifungal agent that inhibits the growth
of pathogenic dermatophytes, yeasts, and Malassezia furfur. Ciclopirox
exhibits fungicidal activity in vitro against isolates of Trichophyton
rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum,
Microsporum canis, and Candida albicans.
Pharmacokinetic studies in men with radiolabeled ciclopirox solution in
polyethylene glycol 400 showed an average of 1.3% absorption of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
dose when it was applied topically to 750 cm2 on the back followed by
occlusion for 6 hours. The biological half-life was 1.7 hours and
excretion occurred via the kidney. Two days after application only
0.01% of the dose applied could be found in the urine. Fecal excretion
was negligible. Autoradiographic studies with human cadaver skin
showed that ciclopirox penetrates into the hair and through the
epidermis and hair follicles into the sebaceous glands and dermis, while
a portion of the drug remains in the stratum corneum.
In vitro penetration studies in frozen or fresh excised human cadaver
and pig skin indicated that the penetration of LOPROX® Lotion is
equivalent to that of Loprox® Cream (ciclopirox olamine) 0.77%.
Therapeutic equivalence of cream and lotion formulations also was
indicated by studies of experimentally induced guinea pig and human
trichophytosis.
INDICATIONS AND USAGE
LOPROX® Lotion is indicated for the topical treatment of the following
dermal infections: tinea pedis, tinea cruris and tinea corporis due to
Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton
floccosum, and Microsporum canis; cutaneous candidiasis (moniliasis)
due to Candida albicans; and tinea (pityriasis) versicolor due to
Malassezia furfur.
CONTRAINDICATIONS
LOPROX® Lotion is contraindicated in individuals who have shown
hypersensitivity to any of its components.
WARNINGS
General
LOPROX® Lotion is not for ophthalmic use.
Keep out of reach of children.
PRECAUTIONS
If a reaction suggesting sensitivity or chemical irritation should occur
with the use of LOPROX® Lotion, treatment should be discontinued and
appropriate therapy instituted.
Information for Patients
The patient should be told to:
1 . Use the medication for the full treatment time even though
signs/symptoms may have improved and notify the physician if there
is no improvement after four weeks.
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4
2. Inform the physician if the area of application shows signs of
increased irritation (redness, itching, burning, blistering, swelling,
oozing) indicative of possible sensitization.
3. Avoid the use of occlusive wrappings or dressings.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A carcinogenicity study in female mice dosed cutaneously twice per
week for 50 weeks followed by a 6-month drug-free observation period
prior to necropsy revealed no evidence of tumors at the application site.
The following in vitro and in vivo genotoxicity tests have been
conducted with ciclopirox olamine: studies to evaluate gene mutation in
the Ames Salmonella/Mammalian Microsome Assay (negative) and
Yeast Saccharomyces Cerevisiae Assay (negative) and studies to
evaluate chromosome aberrations in vivo in the Mouse Dominant Lethal
Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative).
The following battery of in vitro genotoxicity tests were conducted with
ciclopirox: a chromosome aberration assay in V79 Chinese Hamster
Cells, with and without metabolic activation (positive); a gene mutation
assay in the HGPRT - test with V79 Chinese Hamster Cells (negative);
and a primary DNA damage assay (i.e., unscheduled DNA Synthesis
Assay in A549 Human Cells (negative)). An in vitro Cell Transformation
Assay in BALB/C3T3 Cells was negative for cell transformation. In an
in vivo Chinese Hamster Bone Marrow Cytogenetic Assay, ciclopirox
was negative for chromosome aberrations at 5000 mg/kg.
Pregnancy Category B
Reproduction studies have been performed in the mouse, rat, rabbit,
and monkey, via various routes of administration, at doses 10 times or
more the topical human dose and have revealed no significant evidence
of impaired fertility or harm to the fetus due to ciclopirox. There are,
however, no adequate or well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly
needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Caution
should be exercised when LOPROX® Lotion is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 10 years
have not been established.
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5
ADVERSE REACTIONS
In the controlled clinical trial with 89 patients using LOPROX® Lotion and
89 patients using the vehicle, the incidence of adverse reactions was
low. Those considered possibly related to treatment or occurring in
more than one patient were pruritus, which occurred in two patients
using ciclopirox lotion and one patient using the lotion vehicle, and
burning, which occurred in one patient using ciclopirox lotion.
DOSAGE AND ADMINISTRATION
Gently massage LOPROX® Lotion into the affected and surrounding
skin areas twice daily, in the morning and evening. Clinical improvement
with relief of pruritus and other symptoms usually occurs within the first
week of treatment. If a patient shows no clinical improvement after four
weeks of treatment with LOPROX® Lotion the diagnosis should be
redetermined. Patients with tinea versicolor usually exhibit clinical and
mycological clearing after two weeks of treatment.
HOW SUPPLIED
Loprox® Lotion (ciclopirox) 0.77% is supplied in 30 ml bottles (NDC
99207-008-30), 60 ml bottles (NDC 99207-008-60).
Bottle space provided to allow for vigorous shaking before each
use.
Store between 5º - 25ºC (41º - 77ºF).
Covered by US Patent 3,883,545
Prescribing Information as of September 2001
Manufactured for:
MEDICIS, The Dermatology Company®
Scottsdale, AZ 85258
by: West Pharmaceutical Services Lakewood, Inc.
Lakewood, NJ 08701
REG TM THE AVENTIS GROUP
00830-08D
The Dermatology Company
®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:01.113074
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19824slr009_loprox_lbl.pdf', 'application_number': 19824, 'submission_type': 'SUPPL ', 'submission_number': 9}
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Page 2
9179714
630002-14
TABLETS
PLENDIL
(felodipine)
EXTENDED-RELEASE TABLETS
DESCRIPTION
PLENDIL* (felodipine) is a calcium antagonist (calcium channel blocker). Felodipine is a
dihydropyridine derivative that is chem-ically described as ± ethyl methyl 4-(2,3-dichlorophenyl)-1,4-
dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Its empirical formula is C18H19Cl2NO4 and its
structural formula is:
Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble
in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture.
Tablets PLENDIL provide extended release of felodipine. They are available as tablets containing 2.5
mg, 5 mg, or 10 mg of felodipine for oral administration. In addition to the active ingredient
felodipine, the tablets contain the following inactive ingredients: Tablets PLENDIL 2.5 mg —
hydroxypropyl cellulose, lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow
iron oxide, and other ingredients. Tablets PLENDIL 5 mg and 10 mg — cellulose, red and yellow
oxide, lactose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.
CLINICAL PHARMACOLOGY
Mechanism of Action
Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel
blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for
dihydropyridine binding sites, blocks voltage-dependent Ca++ currents in vascular smooth muscle and
cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
In vitro studies show that the effects of felodipine on contractile processes are selective, with greater
effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in
vitro, but such effects have not been seen in intact animals.
The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of
peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular
Effects). With the exception of a mild diuretic effect seen in several animal species and man, the
effects of felodipine are accounted for by its effects on peripheral vascular resistance.
Pharmacokinetics and Metabolism
Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-
pass metabolism. The systemic bioavailability of PLENDIL is approximately 20%. Mean peak
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Page 3
concentrations following the administration of PLENDIL are reached in 2.5 to 5 hours. Both peak
plasma concentration and the area under the plasma concentration time curve (AUC) increase linearly
with doses up to 20 mg. Felodipine is greater than 99% bound to plasma proteins.
Following intravenous administration, the plasma concentration of felodipine declined triexponentially
with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. The mean contributions of
the three individual phases to the overall AUC were 15, 40, and 45%, respectively, in the order of
increasing t 1/2.
Following oral administration of the immediate-release formulation, the plasma level of felodipine also
declined polyexponentially with a mean terminal t1/2 of 11 to 16 hours. The mean peak and trough
steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given
once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The trough plasma
concentration of felodipine in most individuals was substantially below the concentration needed to
effect a half-maximal decline in blood pressure (EC50) [4–6 nmol/L for felodipine], thus precluding
once-a-day dosing with the immediate-release formulation.
Following administration of a 10-mg dose of PLENDIL, the extended-release formulation, to young,
healthy volunteers, mean peak and trough steady-state plasma concentrations of felodipine were 7 and
2 nmol/L, respectively. Corresponding values in hypertensive patients (mean age 64) after a 20-mg
dose of PLENDIL were 23 and 7 nmol/L. Since the EC50 for felodipine is 4 to 6 nmol/L, a 5- to 10-mg
dose of PLENDIL in some patients, and a 20-mg dose in others, would be expected to provide an
antihypertensive effect that persists for 24 hours (see Cardiovascular Effects below and DOSAGE
AND ADMINISTRATION).
The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the
apparent volume of distribution is about 10 L/kg.
Following an oral or intravenous dose of 14C-labeled felodipine in man, about 70% of the dose of
radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine is
recovered in the urine and feces (< 0.5%). Six metabolites, which account for 23% of the oral dose,
have been identified; none has significant vasodilating activity.
Following administration of PLENDIL to hypertensive patients, mean peak plasma concentrations at
steady state are about 20% higher than after a single dose. Blood pressure response is correlated with
plasma concentrations of felodipine.
The bioavailability of PLENDIL is influenced by the presence of food. When administered either with
a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When
PLENDIL was administered after a light meal (orange juice, toast, and cereal), however, there is no
effect on felodipine’s pharmacokinetics. The bioavailability of felodipine was increased approximately
two-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of
PLENDIL. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a
lesser extent than that seen with felodipine.
Geriatric Use— Plasma concentrations of felodipine, after a single dose and at steady state, increase
with age. Mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of
young volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the
elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young
and the elderly.
Hepatic Dysfunction— In patients with hepatic disease, the clearance of felodipine was reduced to
about 60% of that seen in normal young volunteers.
Renal impairment does not alter the plasma concentration profile of felodipine; although higher
concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these
are inactive.
Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.
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Cardiovascular Effects
Following administration of PLENDIL, a reduction in blood pressure generally occurs within 2 to 5
hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough
reductions in diastolic blood pressure approximately 40–50% of peak reductions. The antihypertensive
effect is dose dependent and correlates with the plasma concentration of felodipine.
A reflex increase in heart rate frequently occurs during the first week of therapy; this increase
attenuates over time. Heart rate increases of 5–10 beats per minute may be seen during chronic dosing.
The increase is inhibited by beta-blocking agents.
The P-R interval of the ECG is not affected by felodipine when administered alone or in combination
with a beta-blocking agent. Felodipine alone or in combination with a beta-blocking agent has been
shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction
(P-R, P-Q, and H-V intervals).
In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no
symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in
this population (see PRECAUTIONS).
Renal/Endocrine Effects
Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains
unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of
therapy. No significant effects on serum electrolytes were observed during short- and long-term
therapy.
In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been
observed.
Clinical Studies
Felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in
six placebo-controlled, dose response studies using either immediate-release or extended-release
dosage forms. These studies enrolled over 800 patients on active treatment, at total daily doses ranging
from 2.5 to 20 mg. In those studies felodipine was administered either as monotherapy or was added to
beta blockers. The results of the 2 studies with PLENDIL given once daily as monotherapy are shown
in the table below:
MEAN REDUCTIONS IN BLOOD PRESSURE (mmHg)*
Systolic/Diastolic
Mean Peak
Mean Trough
Trough/Peak
Dose
N
Response
Response Ratios (%s)
Study 1 (8 weeks)
2.5 mg
68
9.4/4.7
2.7/2.5
29/53
5 mg
69
9.5/6.3
2.4/3.7 25/59
10 mg
67
18.0/10.8 10.0/6.0 56/56
Study 2 (4 weeks)
10 mg
50
5.3/7.2
1.5/3.2 33/40**
20 mg
50
11.3/10.2 4.5/3.2
43/34**
* Placebo response subtracted
** Different number of patients available for peak and trough
measurements
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INDICATIONS AND USAGE
PLENDIL is indicated for the treatment of hypertension.
PLENDIL may be used alone or concomitantly with other antihypertensive agents.
CONTRAINDICATIONS
PLENDIL is contraindicated in patients who are hypersensitive to this product.
PRECAUTIONS
General
Hypotension— Felodipine, like other calcium antagonists, may occasionally precipitate significant
hypotension and, rarely, syncope. It may lead to reflex tachycardia which in susceptible individuals
may precipitate angina pectoris. (See ADVERSE REACTIONS.)
Heart Failure— Although acute hemodynamic studies in a small number of patients with NYHA Class
II or III heart failure treated with felodipine have not demonstrated negative inotropic effects, safety in
patients with heart failure has not been established. Caution, therefore, should be exercised when using
PLENDIL in patients with heart failure or compromised ventricular function, particularly in
combination with a beta blocker.
Patients with Impaired Liver Function—Patients with impaired liver function may have elevated
plasma concentrations of felodipine and may respond to lower doses of PLENDIL; therefore, a starting
dose of 2.5 mg once a day is recommended. These patients should have their blood pressure monitored
closely during dosage adjustment of PLENDIL. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION.)
Peripheral Edema— Peripheral edema, generally mild and not associated with generalized fluid
retention, was the most common adverse event in the clinical trials. The incidence of peripheral edema
was both dose and age dependent. Frequency of peripheral edema ranged from about 10% in patients
under 50 years of age taking 5 mg daily to about 30% in those over 60 years of age taking 20 mg daily.
This adverse effect generally occurs within 2–3 weeks of the initiation of treatment.
Information for Patients
Patients should be instructed to take PLENDIL whole and not to crush or chew the tablets. They
should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene
decreases its incidence and severity.
NOTE: As with many other drugs, certain advice to patients being treated with PLENDIL is warranted.
This information is intended to aid in the safe and effective use of this medication. It is not a disclosure
of all possible adverse or intended effects.
Drug Interactions
CYP3A4 Inhibitors—Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors
(eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to
several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or
due to a decrease in metabolism. These increases in concentration may lead to increased effects,
(lower blood pressure and increased heart rate). These effects have been observed with co-
administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4
inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be
taken. The following specific interactions have been reported:
Itraconazole—Co-administration of another extended release formulation of felodipine with
itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the
Cmax, and 2-fold prolongation in the half-life of felodipine.
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Erythromycin—Co-administration of felodipine (PLENDIL) with erythromycin resulted in
approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of
felodipine.
Grapefruit juice—Co-administration of felodipine with grapefruit juice resulted in more than 2-fold
increase in the AUC and Cmax, but no prolongation in the half-life of felodipine.
Cimetidine—Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor)
resulted in an increase of approximately 50% in the AUC and the Cmax, of felodipine.
Beta-Blocking Agents— A pharmacokinetic study of felodipine in conjunction with metoprolol
demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and Cmax of
metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical
trials, however, beta blockers including metoprolol were concurrently administered with felodipine and
were well tolerated.
Digoxin— When given concomitantly with PLENDIL the pharmacokinetics of digoxin in patients with
heart failure were not significantly altered.
Anticonvulsants— In a pharmacokinetic study, maximum plasma concentrations of felodipine were
considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin,
carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the
felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in
healthy volunteers. Since a clinically significant interaction may be anticipated, alternative
antihypertensive therapy should be considered in these patients.
Other Concomitant Therapy— In healthy subjects there were no clinically significant interactions
when felodipine was given concomitantly with indomethacin or spironolactone.
Interaction with Food— See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to
61 times** the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the
incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated
male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day
(61 times** the maximum recommended human dose on a mg/m 2 basis). Felodipine, at the doses
employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a
corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is
possibly secondary to these hormonal effects which have not been observed in man.
In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia
compared to control was observed in the esophageal groove of male and female rats in all dose groups.
No other drug-related esophageal or gastric pathology was observed in the rats or with chronic
administration in mice and dogs. The latter species, like man, has no anatomical structure comparable
to the esophageal groove.
Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times** the
maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99
weeks in females.
Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in
the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse
micronucleus test at oral doses up to 2500 mg/kg (1100 times** the maximum recommended human
dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome aberration assay.
A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day
(up to 24 times** the maximum recommended human dose on a mg/m2 basis) showed no significant
effect of felodipine on reproductive performance.
** Based on patient weight of 50 kg
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Pregnancy
Pregnancy Category C.
Teratogenic Effects— Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3, and 4.6
mg/kg/day (from 0. 8 to 8 times** the maximum recommended human dose on a mg/m2 basis) showed
digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in
the fetuses. The frequency and severity of the changes appeared dose related and were noted even at
the lowest dose. These changes have been shown to occur with other members of the dihydropyridine
class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not
observed in rats given felodipine.
In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was
observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.
Nonteratogenic Effects— A prolongation of parturition with difficult labor and an increased frequency
of fetal and early postnatal deaths were observed in rats administered doses of 9.6 mg/kg/day (8
times** the maximum human dose on a mg/m2 basis) and above.
Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant
rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human
dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation.
Similar changes in the mammary glands were not observed in rats or monkeys.
There are no adequate and well-controlled studies in pregnant women. If felodipine is used during
pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the
potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of
felodipine on labor and delivery and on the mammary glands of pregnant females.
Nursing Mothers
It is not known whether this drug is secreted in human milk and because of the potential for serious
adverse reactions from felodipine in the infant, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
** Based on patient weight of 50 kg
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients.
Pharmacokinetics, however, indicate that the availability of felodipine is increased in older patients
(see CLINICAL PHARMACOLOGY, Geriatric Use). In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
In controlled studies in the United States and overseas, approximately 3000 patients were treated with
felodipine as either the extended-release or the immediate-release formulation.
The most common clinical adverse events reported with PLENDIL administered as monotherapy at the
recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache.
Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of
therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse
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Page 8
event occurred in about 6% of the patients receiving PLENDIL, principally for peripheral edema,
headache, or flushing.
Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of
2.5 mg to 10 mg once a day (PLENDIL, N = 861; Placebo, N = 334), without regard to causality, are
compared to placebo and are listed by dose in the table below. These events are reported from
controlled clinical trials with patients who were randomized to a fixed dose of PLENDIL or titrated
from an initial dose of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been evaluated in
some clinical studies. Although the antihypertensive effect of PLENDIL is increased at 20 mg once a
day, there is a disproportionate increase in adverse events, especially those associated with
vasodilatory effects (see DOSAGE AND ADMINISTRATION).
Percent of Patients with Adverse Events in Controlled Trials* of PLENDIL (N = 861) as
Monotherapy without Regard to Causality (Incidence of discontinuations shown in parentheses)
Body System
Placebo
2.5 mg 5 mg
10 mg
Adverse Events
N = 334
N = 255 N = 581
N = 408
Body as a Whole
Peripheral Edema
3.3 (0.0) 2.0 (0.0) 8.8 (2.2) 17.4 (2.5)
Asthenia
3.3 (0.0) 3.9 (0.0) 3.3 (0.0)
2.2 (0.0)
Warm Sensation
0.0 (0.0) 0.0 (0.0) 0.9 (0.2)
1.5 (0.0)
Cardiovascular
Palpitation
2.4 (0.0) 0.4 (0.0) 1.4 (0.3)
2.5 (0.5)
Digestive
Nausea
1.5 (0.9) 1.2 (0.0) 1.7 (0.3)
1.0 (0.7)
Dyspepsia
1.2 (0.0) 3.9 (0.0) 0.7 (0.0)
0.5 (0.0)
Constipation
0.9 (0.0) 1.2 (0.0) 0.3 (0.0)
1.5 (0.2)
Nervous
Headache
10.2 (0.9) 10.6 (0.4) 11.0 (1.7)
14.7 (2.0)
Dizziness
2.7 (0.3) 2.7 (0.0) 3.6 (0.5)
3.7 (0.5)
Paresthesia
1.5 (0.3) 1.6 (0.0) 1.2 (0.0)
1.2 (0.2)
Respiratory
Upper Respiratory
Infection
1.8 (0.0) 3.9 (0.0) 1.9 (0.0)
0.7 (0.0)
Cough
0.3 (0.0) 0.8 (0.0) 1.2 (0.0)
1.7 (0.0)
Rhinorrhea
0.0 (0.0) 1.6 (0.0) 0.2 (0.0)
0.2 (0.0)
Sneezing
0.0 (0.0) 1.6 (0.0) 0.0 (0.0)
0.0 (0.0)
Skin
Rash
0.9 (0.0) 2.0 (0.0) 0.2 (0.0)
0.2 (0.0)
Flushing
0.9 (0.3) 3.9 (0.0) 5.3 (0.7)
6.9 (1.2)
*Patients in titration studies may have been exposed to more than
one dose level of PLENDIL.
Adverse events that occurred in 0.5 up to 1.5% of patients who received PLENDIL in all controlled
clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse
events that occurred at a lower rate, or events reported during marketing experience (those lower rate
events are in italics) are listed below. These events are listed in order of decreasing severity within
each category, and the relationship of these events to administration of PLENDIL is uncertain: Body as
a Whole: Chest pain, facial edema, flu-like illness; Cardiovascular: Myocardial infarction,
hypotension, syncope, angina pectoris, arrhythmia, tachycardia, premature beats; Digestive:
Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation; Endocrine:
Gynecomastia; Hematologic: Anemia; Metabolic: ALT (SGPT) increased; Musculoskeletal:
Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain;
Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence,
decreased libido; Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis,
respiratory infection; Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis;
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Page 9
Special Senses: Visual disturbances; Urogenital: Impotence, urinary frequency, urinary urgency,
dysuria, polyuria.
Gingival Hyperplasia— Gingival hyperplasia, usually mild, occurred in < 0.5% of patients in
controlled studies. This condition may be avoided or may regress with improved dental hygiene. (See
PRECAUTIONS, Information for Patients.)
Clinical Laboratory Test Findings
Serum Electrolytes— No significant effects on serum electrolytes were observed during short- and
long-term therapy (see CLINICAL PHARMACOLOGY, Renal/Endocrine Effects).
Serum Glucose— No significant effects on fasting serum glucose were observed in patients treated
with PLENDIL in the U.S. controlled study.
Liver Enzymes—1 of 2 episodes of elevated serum transaminases decreased once drug was
discontinued in clinical studies; no follow-up was available for the other patient.
OVERDOSAGE
Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and
2250 mg/kg in male and female rats, respectively, caused significant lethality.
In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and
spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on
admission to hospital; he subsequently recovered without significant sequelae.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension
and possibly bradycardia.
If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed
supine with the legs elevated. The administration of intravenous fluids may be useful to treat
hypotension due to overdosage with calcium antagonists. In case of accompanying bradycardia,
atropine (0.5–1 mg) should be administered intravenously. Sympathomimetic drugs may also be given
if the physician feels they are warranted.
It has not been established whether felodipine can be removed from the circulation by hemodialysis.
To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-
Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’
Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses,
drug-drug interactions, and unusual drug kinetics in your patient.
DOSAGE AND ADMINISTRATION
The recommended starting dose is 5 mg once a day. Depending on the patient's response, the dosage
can be decreased to 2.5 mg or increased to 10 mg once a day. These adjustments should occur
generally at intervals of not less than 2 weeks. The recommended dosage range is 2.5–10 mg once
daily. In clinical trials, doses above 10 mg daily showed an increased blood pressure response but a
large increase in the rate of peripheral edema and other vasodilatory adverse events (see ADVERSE
REACTIONS). Modification of the recommended dosage is usually not required in patients with renal
impairment.
PLENDIL should regularly be taken either without food or with a light meal (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism). PLENDIL should be swallowed whole and
not crushed or chewed.
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Geriatric Use—Patients over 65 years of age are likely to develop higher plasma concentrations of
felodipine (see CLINICAL PHARMACOLOGY). In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients
should have their blood pressure closely monitored during any dosage adjustment.
Patients with Impaired Liver Function—Patients with impaired liver function may have elevated
plasma concentrations of felodipine and may respond to lower doses of PLENDIL; therefore, patients
should have their blood pressure monitored closely during dosage adjustment of PLENDIL (see
CLINICAL PHARMACOLOGY).
HOW SUPPLIED
No. 3584 — Tablets PLENDIL, 2.5 mg, are sage green, round convex tablets, with code 450 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0450-28 unit dose packages of 100
NDC 0186-0450-58 unit of use bottles of 100
NDC 0186-0450-31 unit of use bottles of 30
No. 3585 — Tablets PLENDIL, 5 mg, are light red-brown, round convex tablets, with code 451 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0451-28 unit dose packages of 100
NDC 0186-0451-58 unit of use bottles of 100
NDC 0186-0451-31 unit of use bottles of 30
No. 3586 — Tablets PLENDIL, 10 mg, are red-brown, round convex tablets, with code 452 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0452-28 unit dose packages of 100
NDC 0186-0452-58 unit of use bottles of 100
NDC 0186-0452-31 unit of use bottles of 30
Storage
Store below 30°C (86°F). Keep container tightly closed. Protect from light.
All trademarks are the property of the AstraZeneca group
©AstraZeneca 2000
Revised September 2000
Manufactured for: AstraZeneca LP
Wilmington, DE 19850
By: Merck & Co., Inc., Whitehouse Station, NJ, 08889 USA
9179714
630002-14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Doug Throckmorton
5/22/02 03:51:10 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:01.151028
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19834s17lbl.pdf', 'application_number': 19834, 'submission_type': 'SUPPL ', 'submission_number': 17}
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NDA 19-834/S-022
Page 3
9179716
630002-16
PLENDIL
(felodipine)
EXTENDED-RELEASE TABLETS
DESCRIPTION
PLENDIL (felodipine) is a calcium antagonist (calcium channel blocker). Felodipine is a
dihydropyridine derivative that is chemically described as ± ethyl methyl 4-(2,3-dichlorophenyl)-1,4-
dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Its empirical formula is C18H19Cl2NO4 and its
structural formula is:
Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble
in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture.
Tablets PLENDIL provide extended release of felodipine. They are available as tablets containing 2.5
mg, 5 mg, or
10 mg of felodipine for oral administration. In addition to the active ingredient felodipine, the tablets
contain the following inactive ingredients: Tablets PLENDIL 2.5 mg — hydroxypropyl cellulose,
lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow iron oxide, and other
ingredients. Tablets PLENDIL 5 mg and 10 mg — cellulose, red and yellow oxide, lactose,
polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.
CLINICAL PHARMACOLOGY
Mechanism of Action
Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel
blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for
dihydropyridine binding sites, blocks voltage-dependent Ca++ currents in vascular smooth muscle and
cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
In vitro studies show that the effects of felodipine on contractile processes are selective, with greater
effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in
vitro, but such effects have not been seen in intact animals.
The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of
peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular
Effects). With the exception of a mild diuretic effect seen in several animal species and man, the
effects of felodipine are accounted for by its effects on peripheral vascular resistance.
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Page 4
Pharmacokinetics and Metabolism
Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-
pass metabolism. The systemic bioavailability of PLENDIL is approximately 20%. Mean peak
concentrations following the administration of PLENDIL are reached in 2.5 to 5 hours. Both peak
plasma concentration and the area under the plasma concentration time curve (AUC) increase linearly
with doses up to 20 mg. Felodipine is greater than 99% bound to plasma proteins.
Following intravenous administration, the plasma concentration of felodipine declined triexponentially
with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. The mean contributions of
the three individual phases to the overall AUC were 15, 40, and 45%, respectively, in the order of
increasing t1/2.
Following oral administration of the immediate-release formulation, the plasma level of felodipine also
declined polyexponentially with a mean terminal t1/2 of 11 to 16 hours. The mean peak and trough
steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given
once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The trough plasma
concentration of felodipine in most individuals was substantially below the concentration needed to
effect a half-maximal decline in blood pressure (EC50) [4–6 nmol/L for felodipine], thus precluding
once-a-day dosing with the immediate-release formulation.
Following administration of a 10-mg dose of PLENDIL, the extended-release formulation, to young,
healthy volunteers, mean peak and trough steady-state plasma concentrations of felodipine were 7 and
2 nmol/L, respectively. Corresponding values in hypertensive patients (mean age 64) after a 20-mg
dose of PLENDIL were 23 and 7 nmol/L. Since the EC50 for felodipine is 4 to 6 nmol/L, a 5- to 10-
mg dose of PLENDIL in some patients, and a 20-mg dose in others, would be expected to provide an
antihypertensive effect that persists for 24 hours (see Cardiovascular Effects below and DOSAGE
AND ADMINISTRATION).
The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the
apparent volume of distribution is about 10 L/kg.
Following an oral or intravenous dose of 14C-labeled felodipine in man, about 70% of the dose of
radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine is
recovered in the urine and feces (< 0.5%). Six metabolites, which account for 23% of the oral dose,
have been identified; none has significant vasodilating activity.
Following administration of PLENDIL to hypertensive patients, mean peak plasma concentrations at
steady state are about 20% higher than after a single dose. Blood pressure response is correlated with
plasma concentrations of felodipine.
The bioavailability of PLENDIL is influenced by the presence of food. When administered either with
a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When
PLENDIL was administered after a light meal (orange juice, toast, and cereal), however, there is no
effect on felodipine’s pharmacokinetics. The bioavailability of felodipine was increased approximately
two-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of
PLENDIL. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a
lesser extent than that seen with felodipine.
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Page 5
Geriatric Use— Plasma concentrations of felodipine, after a single dose and at steady state, increase
with age. Mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of
young volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the
elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young
and the elderly.
Hepatic Dysfunction— In patients with hepatic disease, the clearance of felodipine was reduced to
about 60% of that seen in normal young volunteers.
Renal impairment does not alter the plasma concentration profile of felodipine; although higher
concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these
are inactive.
Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.
Cardiovascular Effects
Following administration of PLENDIL, a reduction in blood pressure generally occurs within 2 to 5
hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough
reductions in diastolic blood pressure approximately 40–50% of peak reductions. The antihypertensive
effect is dose dependent and correlates with the plasma concentration of felodipine.
A reflex increase in heart rate frequently occurs during the first week of therapy; this increase
attenuates over time. Heart rate increases of 5–10 beats per minute may be seen during chronic dosing.
The increase is inhibited by beta-blocking agents.
The P-R interval of the ECG is not affected by felodipine when administered alone or in combination
with a beta-blocking agent. Felodipine alone or in combination with a beta-blocking agent has been
shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction
(P-R, P-Q, and H-V intervals).
In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no
symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in
this population (see PRECAUTIONS).
Renal/Endocrine Effects
Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains
unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of
therapy. No significant effects on serum electrolytes were observed during short- and long-term
therapy.
In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been
observed.
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Page 6
Clinical Studies
Felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in
six placebo-controlled, dose response studies using either immediate-release or extended-release
dosage forms. These studies enrolled over 800 patients on active treatment, at total daily doses ranging
from 2.5 to 20 mg. In those studies felodipine was administered either as monotherapy or was added to
beta blockers. The results of the 2 studies with PLENDIL given once daily as monotherapy are shown
in the table below:
MEAN REDUCTIONS IN BLOOD PRESSURE (MMHG)*
Systolic/Diastolic
Mean Peak
Mean Trough
Trough/Peak
Dose
N
Response
Response Ratios (%s)
Study 1 (8 weeks)
2.5 mg
68
9.4/4.7
2.7/2.5
29/53
5 mg
69
9.5/6.3
2.4/3.7 25/59
10 mg
67
18.0/10.8 10.0/6.0 56/56
Study 2 (4 weeks)
10 mg
50
5.3/7.2
1.5/3.2 33/40**
20 mg
50
11.3/10.2 4.5/3.2
43/34**
* Placebo response subtracted
** Different number of patients available for peak and trough
measurements
INDICATIONS AND USAGE
PLENDIL is indicated for the treatment of hypertension.
PLENDIL may be used alone or concomitantly with other antihypertensive agents.
CONTRAINDICATIONS
PLENDIL is contraindicated in patients who are hypersensitive to this product.
PRECAUTIONS
General
Hypotension— Felodipine, like other calcium antagonists, may occasionally precipitate significant
hypotension and, rarely, syncope. It may lead to reflex tachycardia which in susceptible individuals
may precipitate angina pectoris. (See ADVERSE REACTIONS.)
Heart Failure— Although acute hemodynamic studies in a small number of patients with NYHA Class
II or III heart failure treated with felodipine have not demonstrated negative inotropic effects, safety in
patients with heart failure has not been established. Caution, therefore, should be exercised when using
PLENDIL in patients with heart failure or compromised ventricular function, particularly in
combination with a beta blocker.
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NDA 19-834/S-022
Page 7
Patients with Impaired Liver Function—Patients with impaired liver function may have elevated
plasma concentrations of felodipine and may respond to lower doses of PLENDIL; therefore, a starting
dose of 2.5 mg once a day is recommended. These patients should have their blood pressure monitored
closely during dosage adjustment of PLENDIL. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION.)
Peripheral Edema— Peripheral edema, generally mild and not associated with generalized fluid
retention, was the most common adverse event in the clinical trials. The incidence of peripheral edema
was both dose and age dependent. Frequency of peripheral edema ranged from about 10% in patients
under 50 years of age taking 5 mg daily to about 30% in those over 60 years of age taking 20 mg daily.
This adverse effect generally occurs within 2–3 weeks of the initiation of treatment.
Information for Patients
Patients should be instructed to take PLENDIL whole and not to crush or chew the tablets. They
should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene
decreases its incidence and severity.
NOTE: As with many other drugs, certain advice to patients being treated with PLENDIL is warranted.
This information is intended to aid in the safe and effective use of this medication. It is not a disclosure
of all possible adverse or intended effects.
Drug Interactions
CYP3A4 Inhibitors—Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors
(eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to
several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or
due to a decrease in metabolism. These increases in concentration may lead to increased effects,
(lower blood pressure and increased heart rate). These effects have been observed with co-
administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4
inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be
taken. The following specific interactions have been reported:
Itraconazole—Co-administration of another extended release formulation of felodipine with
itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the
Cmax, and 2-fold prolongation in the half-life of felodipine.
Erythromycin—Co-administration of felodipine (PLENDIL) with erythromycin resulted in
approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of
felodipine.
Grapefruit juice—Co-administration of felodipine with grapefruit juice resulted in more than 2-fold
increase in the AUC and Cmax, but no prolongation in the half-life of felodipine.
Cimetidine—Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor)
resulted in an increase of approximately 50% in the AUC and the Cmax, of felodipine.
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Page 8
Beta-Blocking Agents— A pharmacokinetic study of felodipine in conjunction with metoprolol
demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and Cmax of
metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical
trials, however, beta blockers including metoprolol were concurrently administered with felodipine and
were well tolerated.
Digoxin— When given concomitantly with PLENDIL the pharmacokinetics of digoxin in patients with
heart failure were not significantly altered.
Anticonvulsants— In a pharmacokinetic study, maximum plasma concentrations of felodipine were
considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin,
carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the
felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in
healthy volunteers. Since a clinically significant interaction may be anticipated, alternative
antihypertensive therapy should be considered in these patients.
Tacrolimus— Felodipine may increase the blood concentration of tacrolimus. When given
concomitantly with felodipine, the tacrolimus blood concentration should be followed and the
tacrolimus dose may need to be adjusted.
Other Concomitant Therapy— In healthy subjects there were no clinically significant interactions
when felodipine was given concomitantly with indomethacin or spironolactone.
Interaction with Food— See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to
61 times** the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the
incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated
male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day
(61 times** the maximum recommended human dose on a mg/m2 basis). Felodipine, at the doses
employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a
corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is
possibly secondary to these hormonal effects which have not been observed in man.
In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia
compared to control was observed in the esophageal groove of male and female rats in all dose groups.
No other drug-related esophageal or gastric pathology was observed in the rats or with chronic
administration in mice and dogs. The latter species, like man, has no anatomical structure comparable
to the esophageal groove.
Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times** the
maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99
weeks in females.
_____________________________
** Based on patient weight of 50 kg
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Page 9
Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in
the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse
micronucleus test at oral doses up to 2500 mg/kg (1100 times** the maximum recommended human
dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome aberration assay.
A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day
(up to 24 times** the maximum recommended human dose on a mg/m2 basis) showed no significant
effect of felodipine on reproductive performance.
Pregnancy:
Pregnancy Category C.
Teratogenic Effects: Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3, and 4.6
mg/kg/day (from 0.8 to 8 times** the maximum recommended human dose on a mg/m2 basis) showed
digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in
the fetuses. The frequency and severity of the changes appeared dose related and were noted even at
the lowest dose. These changes have been shown to occur with other members of the dihydropyridine
class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not
observed in rats given felodipine.
In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was
observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.
Nonteratogenic Effects A prolongation of parturition with difficult labor and an increased frequency
of fetal and early postnatal deaths were observed in rats administered doses of 9.6 mg/kg/day (8
times** the maximum human dose on a mg/m2 basis) and above.
Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant
rabbits, was found with doses greater than or equal to 1.2 mg/kg/day
_____________________________
** Based on patient weight of 50 kg
(2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits
and regressed during lactation.
Similar changes in the mammary glands were not observed in rats or monkeys.
There are no adequate and well-controlled studies in pregnant women. If felodipine is used during
pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the
potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of
felodipine on labor and delivery and on the mammary glands of pregnant females.
Nursing Mothers
It is not known whether this drug is secreted in human milk and because of the potential for serious
adverse reactions from felodipine in the infant, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
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Geriatric Use:
Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients.
Pharmacokinetics, however, indicate that the availability of felodipine is increased in older patients
(see CLINICAL PHARMACOLOGY, Geriatric Use). In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
In controlled studies in the United States and overseas, approximately 3000 patients were treated with
felodipine as either the extended-release or the immediate-release formulation.
The most common clinical adverse events reported with PLENDIL administered as monotherapy at the
recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache.
Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of
therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse
event occurred in about 6% of the patients receiving PLENDIL, principally for peripheral edema,
headache, or flushing.
Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of
2.5 mg to
10 mg once a day (PLENDIL, N = 861; Placebo, N = 334), without regard to causality, are compared
to placebo and are listed by dose in the table below. These events are reported from controlled clinical
trials with patients who were randomized to a fixed dose of PLENDIL or titrated from an initial dose
of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been evaluated in some clinical studies.
Although the antihypertensive effect of PLENDIL is increased at 20 mg once a day, there is a
disproportionate increase in adverse events, especially those associated with vasodilatory effects (see
DOSAGE AND ADMINISTRATION).
Percent of Patients with Adverse Events in Controlled Trials* of PLENDIL (N = 861) as
Monotherapy without Regard to Causality (Incidence of discontinuations shown in parentheses)
Body System
Placebo
2.5 mg 5 mg
10 mg
Adverse Events
N = 334
N = 255 N = 581
N = 408
Body as a Whole
Peripheral Edema
3.3 (0.0)
2.0 (0.0) 8.8 (2.2) 17.4 (2.5)
Asthenia
3.3 (0.0)
3.9 (0.0) 3.3 (0.0)
2.2 (0.0)
Warm Sensation
0.0 (0.0)
0.0 (0.0) 0.9 (0.2)
1.5 (0.0)
Cardiovascular
Palpitation
2.4 (0.0)
0.4 (0.0) 1.4 (0.3)
2.5 (0.5)
Digestive
Nausea
1.5 (0.9)
1.2 (0.0) 1.7 (0.3)
1.0 (0.7)
Dyspepsia
1.2 (0.0) 3.9 (0.0) 0.7 (0.0)
0.5 (0.0)
Constipation
0.9 (0.0) 1.2 (0.0) 0.3 (0.0)
1.5 (0.2)
Nervous
Headache
10.2 (0.9) 10.6 (0.4) 11.0 (1.7)
14.7 (2.0)
Dizziness
2.7 (0.3) 2.7 (0.0) 3.6 (0.5)
3.7 (0.5)
Paresthesia
1.5 (0.3) 1.6 (0.0) 1.2 (0.0)
1.2 (0.2)
Respiratory
Upper Respiratory
Infection
1.8 (0.0)
3.9 (0.0) 1.9 (0.0)
0.7 (0.0)
Cough
0.3 (0.0) 0.8 (0.0) 1.2 (0.0)
1.7 (0.0)
Rhinorrhea
0.0 (0.0) 1.6 (0.0) 0.2 (0.0)
0.2 (0.0)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-834/S-022
Page 11
Sneezing
0.0 (0.0)
1.6 (0.0) 0.0 (0.0)
0.0 (0.0)
Skin
Rash
0.9 (0.0) 2.0 (0.0) 0.2 (0.0)
0.2 (0.0)
Flushing
0.9 (0.3)
3.9 (0.0) 5.3 (0.7)
6.9 (1.2)
*Patients in titration studies may have been exposed to more than
one dose level of PLENDIL.
Adverse events that occurred in 0.5 up to 1.5% of patients who received PLENDIL in all controlled
clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse
events that occurred at a lower rate, or events reported during marketing experience (those lower rate
events are in italics) are listed below. These events are listed in order of decreasing severity within
each category, and the relationship of these events to administration of PLENDIL is uncertain: Body as
a Whole: Chest pain, facial edema, flu-like illness; Cardiovascular: Myocardial infarction,
hypotension, syncope, angina pectoris, arrhythmia, tachycardia, premature beats; Digestive:
Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation; Endocrine:
Gynecomastia; Hematologic: Anemia; Metabolic: ALT (SGPT) increased; Musculoskeletal:
Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain;
Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence,
decreased libido; Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis,
respiratory infection; Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis;
Special Senses: Visual disturbances; Urogenital: Impotence, urinary frequency, urinary urgency,
dysuria, polyuria.
Gingival Hyperplasia— Gingival hyperplasia, usually mild, occurred in < 0.5% of patients in
controlled studies. This condition may be avoided or may regress with improved dental hygiene. (See
PRECAUTIONS, Information for Patients.)
Clinical Laboratory Test Findings
Serum Electrolytes— No significant effects on serum electrolytes were observed during short- and
long-term therapy (see CLINICAL PHARMACOLOGY, Renal/Endocrine Effects).
Serum Glucose— No significant effects on fasting serum glucose were observed in patients treated
with PLENDIL in the U.S. controlled study.
Liver Enzymes—1 of 2 episodes of elevated serum transaminases decreased once drug was
discontinued in clinical studies; no follow-up was available for the other patient.
OVERDOSAGE
Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and
2250 mg/kg in male and female rats, respectively, caused significant lethality.
In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and
spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on
admission to hospital; he subsequently recovered without significant sequelae.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension
and possibly bradycardia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-834/S-022
Page 12
If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed
supine with the legs elevated. The administration of intravenous fluids may be useful to treat
hypotension due to overdosage with calcium antagonists. In case of accompanying bradycardia,
atropine (0.5–1 mg) should be administered intravenously. Sympathomimetic drugs may also be given
if the physician feels they are warranted.
It has not been established whether felodipine can be removed from the circulation by hemodialysis.
To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-
Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’
Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses,
drug-drug interactions, and unusual drug kinetics in your patient.
DOSAGE AND ADMINISTRATION
The recommended starting dose is 5 mg once a day. Depending on the patient's response, the dosage
can be decreased to 2.5 mg or increased to 10 mg once a day. These adjustments should occur
generally at intervals of not less than 2 weeks. The recommended dosage range is 2.5–10 mg once
daily. In clinical trials, doses above 10 mg daily showed an increased blood pressure response but a
large increase in the rate of peripheral edema and other vasodilatory adverse events (see ADVERSE
REACTIONS). Modification of the recommended dosage is usually not required in patients with renal
impairment.
PLENDIL should regularly be taken either without food or with a light meal (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism). PLENDIL should be swallowed whole and
not crushed or chewed.
Geriatric Use—Patients over 65 years of age are likely to develop higher plasma concentrations of
felodipine (see CLINICAL PHARMACOLOGY). In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients
should have their blood pressure closely monitored during any dosage adjustment.
Patients with Impaired Liver Function—Patients with impaired liver function may have elevated
plasma concentrations of felodipine and may respond to lower doses of PLENDIL; therefore, patients
should have their blood pressure monitored closely during dosage adjustment of PLENDIL (see
CLINICAL PHARMACOLOGY).
HOW SUPPLIED
No. 3584 — Tablets PLENDIL, 2.5 mg, are sage green, round convex tablets, with code 450 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0450-28 unit dose packages of 100
NDC 0186-0450-58 unit of use bottles of 100
No. 3585 — Tablets PLENDIL, 5 mg, are light red-brown, round convex tablets, with code 451 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0451-28 unit dose packages of 100
NDC 0186-0451-58 unit of use bottles of 100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-834/S-022
Page 13
No. 3586 — Tablets PLENDIL, 10 mg, are red-brown, round convex tablets, with code 452 on one
side and PLENDIL on the other. They are supplied as follows:
NDC 0186-0452-28 unit dose packages of 100
NDC 0186-0452-58 unit of use bottles of 100
Storage:
Store below 30°C (86°F). Keep container tightly closed. Protect from light.
PLENDIL is a trademark of the AstraZeneca group of companies
©AstraZeneca 2000,2003
Rev 11/03
Manufactured for: AstraZeneca LP
Wilmington, DE 19850
By: Merck & Co., Inc., Whitehouse Station, NJ, 08889 USA
9179716
630002-16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19834slr022_plendil_lbl.pdf', 'application_number': 19834, 'submission_type': 'SUPPL ', 'submission_number': 22}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/19-839S026_Zoloft_prntlbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 26}
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1
ENCLOSURE
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
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2
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral
concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to downregulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied
in subjects administered a single dose with and without food. For the tablet, AUC was slightly
increased when drug was administered with food but the Cmax was 25% greater, while the time
to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For
the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
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3
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age
(11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline
AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr.
Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower
AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data
suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights,
especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND
ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
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4
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in
older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2
was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Overall,
these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression
Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was
not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
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5
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 points units on the
CYBOCS total score which was significantly greater than the 3 point unit reduction for placebo
patients. Analyses for age and gender effects on outcome did not suggest any differential
responsiveness on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a
52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to continuation
of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation
due to relapse or insufficient clinical response. Response during the single-blind phase was
defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very
much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-
blind phase was defined as the following conditions being met (on three consecutive visits for 1
and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum
of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s
condition in the investigator’s judgment, to justify alternative treatment. Insufficient clinical
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6
response indicated a worsening of the patient’s condition that resulted in study discontinuation,
as assessed by the investigator. Patients receiving continued ZOLOFT treatment experienced a
significantly lower rate of discontinuation due to relapse or insufficient clinical response over the
subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in
male and female subjects.
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
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Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in these
trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this apparent
gender interaction is unknown at this time. There was insufficient information to determine the
effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria
for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal
phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
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8
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to
100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day) to
placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
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Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was shown
to be statistically significantly more effective than placebo as measured by the BSPS total score
and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have
significantly more responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There
was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT® (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of outpatients whose diagnoses corresponded most closely to the
DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following
8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled
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trial. The usefulness of the drug in patients receiving ZOLOFT for extended periods should be
reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder, with or without
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about the
implications or consequences of the attacks, and/or a significant change in behavior related to the
attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in panic disorder patients
whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials
under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
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relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of outpatients whose diagnosis met criteria for the DSM-III-R category
of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on
exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in patients with PTSD for up to 28 weeks
following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial.
Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD).
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV
category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
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work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of outpatients with a diagnosis of social anxiety disorder as defined by
DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is
excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in patients with social anxiety disorder for up
to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-controlled
trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-evaluate
the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
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WARNINGS
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT® (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT® (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were
excluded from clinical studies during the product’s premarket testing. No seizures were observed
among approximately 3000 patients treated with ZOLOFT in the development program for major
depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age)
exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Suicide–The possibility of a suicide attempt is inherent in major depressive disorder and may
persist until significant remission occurs. Close supervision of high risk patients should
accompany initial drug therapy. Prescriptions for ZOLOFT should be written for the smallest
quantity of tablets consistent with good patient management, in order to reduce the risk of
overdose.
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Because of the well-established comorbidity between OCD, panic disorder, PTSD, PMDD or
social anxiety disorder and major depressive disorder, the same precautions observed when
treating patients with major depressive disorder should be observed when treating patients with
OCD, panic disorder, PTSD, PMDD or social anxiety disorder.
Weak Uricosuric Effect–ZOLOFT® (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
ZOLOFT has not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during the product’s premarket testing. However, the
electrocardiograms of 774 patients who received ZOLOFT in double-blind trials were evaluated
and the data indicate that ZOLOFT is not associated with the development of significant ECG
abnormalities.
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor route
of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to
that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated
that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the
pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment
(see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible
when ZOLOFT was discontinued. Some cases were possibly due to the syndrome of
inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in
elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
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abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
ZOLOFT:
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
None.
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Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT® (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
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The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs
for which this potential interaction is of greatest concern are those metabolized primarily by 2D6
and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the
treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and
flecainide. The extent to which this interaction is an important clinical problem depends on the
extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-
administered drug. There is variability among the drugs effective in the treatment of major
depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at
lower doses has a less prominent inhibitory effect on 2D6 than some others in the class.
Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Sumatriptan–There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
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citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the
beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans
rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the
maximum recommended human dose (MRHD) on a mg/m2 basis. There was a dose-related
increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the
MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving
the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas
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have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown
significance to humans. There was an increase in follicular adenomas of the thyroid in female
rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT® (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of ZOLOFT in
pediatric patients with major depressive disorder, panic disorder, PTSD, PMDD or Social
Anxiety Disorder has not been established.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
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dose, 52-week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon
clinical response. The mean dose for completers was 157 mg/day. In the acute 12-week pediatric
study and in the 52-week study, ZOLOFT had an adverse event profile generally similar to that
observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
More than 250 patients with major depressive disorder and/or OCD between 6 and 18 years of
age have received ZOLOFT in clinical trials. The adverse event profile observed in these patients
was generally similar to that observed in adult studies with ZOLOFT (see ADVERSE
REACTIONS). As with other SSRIs, decreased appetite and weight loss have been observed in
association with the use of ZOLOFT. Consequently, regular monitoring of weight and growth is
recommended if treatment of a child with an SSRI is to be continued long term. Safety and
effectiveness in pediatric patients below the age of 6 have not been established.
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in
both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.
At baseline the mean weight for children was 39.0kg for sertraline and 38.5kg for placebo. At
baseline the mean weight for adolescents was 61.4kg for sertraline and 62.5kg for placebo.
There was a bigger difference between sertraline and placebo in the proportion of outliers for
clinically important weight loss in children than in adolescents. For children, about 7% had a
weight loss > 7% of body weight compared to none of the placebo patients; for adolescents,
about 2% had a weight loss > 7% of body weight compared to about 1% of placebo patients. A
subset of these patients who completed the randomized controlled trials (sertraline n=100,
placebo n=121) were continued into a 24-week, flexible-dose, open-label, extension study. A
mean weight loss of approximately 0.5kg was seen during the first eight weeks of treatment for
subjects with first exposure to sertraline during the open-label extension study, similar to the
mean weight loss observed among sertraline treated subjects during the first eight weeks of the
randomized controlled trials. The subjects continuing in the open label study began gaining
weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed
34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label,
n=68), had weight gain that was similar to that expected using data from age-adjusted peers.
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Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with
an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the
age of 6 have not been established.
The risks, if any, that may be associated with Zoloft's use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from extrapolation of experience gained with adult patients. In particular, there are no studies
that directly evaluate the effects of long-term sertraline use on the growth, development, and
maturation of children and adolescents. Although there is no affirmative finding to suggest that
sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use.
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall
differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects
relative to those reported in younger subjects (see ADVERSE REACTIONS), and other reported
experience has not identified differences in safety patterns between the elderly and younger
subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled
out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in major
depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that shown
in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in Tables 1
and 2 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-
controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant
hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 26, 199818, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
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estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution of drug and
nondrug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 2
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 2
provides combined data for the pool of studies that are provided separately by indication in
Table 1.
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TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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24
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 1
should be avoided.
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TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Centr. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had an
incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT® (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
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difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 4 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 4
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In approximately over N=250600 pediatric
patients treated with ZOLOFT, the overall profile of adverse events was generally similar to that
seen in adult studies, as shown in Tables 1 and 2. However, the following adverse events, from
controlled trials, not appearing in Tables 1 and 2, were reported at an incidence of at least 2%
and occurred at a rate of at least twice the placebo rate in a controlled trial (N=187281 patients
treated with ZOLOFT): hyperkinesia, twitching, fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, malaise, purpura, weight decrease, concentration impaired, manic
reaction, emotional lability, thinking abnormal, and epistaxis, and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT® (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
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relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
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Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT® (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
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30
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms,
oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity
and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical
features (which in the majority of cases appeared to be reversible with discontinuation of
ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin,
hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT® (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in
fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to
include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence
and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common
signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were
somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
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hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation,
serotonin syndrome, stupor and syncope.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be
increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of
50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the treatment
of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as
the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose
increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of ZOLOFT,
dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
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While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Hepatically Impaired Patients
The use of sertraline in patients with liver disease should be approached with caution. The
effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response to
the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
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33
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments should
be made to maintain patients on the lowest effective dose and patients should be periodically
reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain
the patient on the lowest effective dosage and patients should be periodically reassessed to
determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
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34
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT® (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT® 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 25 mg.
NDC 0049-4960-50
Bottles of 50
ZOLOFT® 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT® 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room
Temperature].
Rx only
2003 Pfizer Inc
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For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Distributed by
Roerig
Division of Pfizer Inc, NY, NY 10017
69-4721-00-5.1
Revised (month) 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19839se5-se5-044,20990se5-010_zoloft_lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,750
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:01.731515
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019835s032lbl.pdf', 'application_number': 19835, 'submission_type': 'SUPPL ', 'submission_number': 32}
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11,753
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1
[FDA Approved Labeling for Zoloft® for the Treatment of Social Anxiety Disorder
Attachment to FDA Approval Letter for NDA 19-839/S-045]
69-4721-00-4.2
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical
name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.
The empirical formula C17H17NCl2•HCl is represented by the following structural formula:
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl
alcohol, and sparingly soluble in ethanol.
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2
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium
phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum
lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum
lake (in 50 mg tablet), hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow
iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following inactive
ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral concentrate
must be diluted prior to administration (see PRECAUTIONS, Information for Patients and DOSAGE
AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake
of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks
the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a
potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no
significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic,
serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has
been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for
other psychotropic drugs. The chronic administration of sertraline was found in animals to downregulate
brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of
major depressive disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to 200 mg for
14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours
post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on
this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after
approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were
demonstrated in a single dose study in which the Cmax and area under the plasma concentration time
curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the
terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single
dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability
of sertraline tablets is approximately equal to an equivalent dose of solution.
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3
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral
solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean
AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were
within the range of 80-125% with the exception of the upper 90% CI limit for Cmax which was
126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in
subjects administered a single dose with and without food. For the tablet, AUC was slightly increased
when drug was administered with food but the Cmax was 25% greater, while the time to reach peak
plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral
concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway of
metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination
half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown
N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and
N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and
glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects,
sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered
radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For
the same period, about 40-45% of the administered radioactivity was accounted for in feces, including
12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax and
Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline showed
that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up
to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter
the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol (see
PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of 61 pediatric
patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of major depressive
disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33).
During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at
that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old group
exhibited a mean sertraline AUC (0-24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean
half-life of 26.2 hr. The 13-17 year old group exhibited a mean sertraline AUC (0-24 hr) of
2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the
6-12 year old group were largely attributable to patients with lower body weights. No gender
associated differences were observed. By comparison, a group of 22 separately studied adults between
18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a
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4
mean sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22%
lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These
data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights,
especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND
ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of
younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in
older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but
not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can affect
the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-
Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who received 50 mg sertraline per
day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater
exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to
desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no
hepatic impairment. There were no significant differences in plasma protein binding observed between
the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have
not been studied. The results suggest that the use of sertraline in patients with liver disease must be
approached with caution. If sertraline is administered to patients with liver impairment, a lower or less
frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is a
minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate to
severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group),
the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not
altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple
dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive disorder
was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for
major depressive disorder. Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of
50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose
study, including ZOLOFT doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated
ZOLOFT to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global
Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose
response relationship for effectiveness.
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5
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of
sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of OCD
was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1-3).
Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline
ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the
mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean reduction
of approximately 4 points on the YBOCS total score which was significantly greater than the mean
reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the
mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean reduction
of approximately 7 points on the YBOCS total score which was significantly greater than the mean
reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the
basis of age or sex.
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The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and
adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at doses of either
25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then titrated over the
next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was
178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to
severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown
Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a
mean reduction of approximately 7 points on the CYBOCS total score which was significantly greater
than the 3 point reduction for placebo patients. Analyses for age and gender effects on outcome did not
suggest any differential responsiveness on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-
week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to
relapse or insufficient clinical response. Response during the single-blind phase was defined as a
decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much
improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was
defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for
condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2)
CGI-I increased by ≥ one point; and (3) worsening of the patient’s condition in the investigator’s
judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to
relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving
placebo. This pattern was demonstrated in male and female subjects.
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was demonstrated in
three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients who had a primary
diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first
week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical response and
toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day,
respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be significantly more
effective than placebo on change from baseline in panic attack frequency and on the Clinical Global
Impression Severity of Illness and Global Improvement scores. The difference between ZOLOFT and
placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks
per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack frequency than
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7
patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship
for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function
of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded
during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to
relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score
of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as
the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R
criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical
response indicated a worsening of the patient’s condition that resulted in study discontinuation, as
assessed by the investigator. Patients receiving continued ZOLOFT treatment experienced a significantly
lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28
weeks compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of PTSD
was established in two multicenter placebo-controlled studies (Studies 1-2) of adult outpatients who
met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years
(Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary
depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first
week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical response and
toleration. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively for
Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2
(CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of
reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of
Event Scale (IES) which measures intrusion and avoidance symptoms. ZOLOFT was shown to be
significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on
the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between patients
receiving ZOLOFT and patients receiving placebo was not statistically significant. One of these
additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the
second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials
were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and
placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference
between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis
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of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men
in these studies. The clinical significance of this apparent gender interaction is unknown at this time.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-
week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of ZOLOFT or
to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open
phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the
CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as
the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score
increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient's condition
in the investigator's judgment. Patients receiving continued ZOLOFT treatment experienced significantly
lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern
was demonstrated in male and female subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment of
PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials
(Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for
Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual
Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study
1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks
prior to the onset of menses. The mean duration of PMDD symptoms for these patients was
approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these
trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of
PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes
assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included
the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of
Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day and
administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the
range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for completers
was 102 mg/day. ZOLOFT administered daily throughout the menstrual cycle was significantly more
effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17
total score, and the CGI-S score, as well as the CGI-I score at endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day in the
late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In
subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle,
on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50
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mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean
ZOLOFT dose for completers was 74 mg/day. ZOLOFT administered in the late luteal phase of the
menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these studies.
Social Anxiety Disorder– The effectiveness of ZOLOFT in the treatment of social
anxiety disorder (also known as social phobia) was established in two multicenter placebo-
controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social
anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200
mg/day) to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week.
Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-
item clinician administered instrument that measures fear, anxiety and avoidance of social
and performance situations, and by (b) the proportion of responders as defined by the
Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or
much improved). ZOLOFT was statistically significantly more effective than placebo as
measured by the LSAS and the percentage of responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-
200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social
Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance
and physiologic response to social or performance situations, (b) the Marks Fear
Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that
measures change in the severity of phobic avoidance and distress, and (c) the CGI-I
responder criterion of ≤ 2. ZOLOFT was shown to be statistically significantly more
effective than placebo as measured by the BSPS total score and fear, avoidance and
physiologic factor scores, as well as the FQ-SPS total score, and to have significantly
more responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of
gender. There was insufficient information to determine the effect of race or age on
outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who
had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-
controlled trial on ZOLOFT 50-200 mg/day were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 24 weeks of observation for relapse.
Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of
Illness (CGI-S) score compared to baseline or study discontinuation due to lack of
efficacy. Patients receiving ZOLOFT continuation treatment experienced a statistically
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significantly lower relapse rate over this 24-week study than patients randomized to
placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT® (sertraline hydrochloride) is indicated for the treatment of
major depressive disorder.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to eight
week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III
category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood
that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at
least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or
retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of
guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal
ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following
8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial.
The usefulness of the drug in patients receiving ZOLOFT for extended periods should be reevaluated
periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e.,
the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with
social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive outpatients
having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R
criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or
images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors
(compulsions) that are recognized by the person as excessive or unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during a 52-
week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up
to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL
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11
PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT for extended periods
should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder, with or without
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected
panic attacks and associated concern about having additional attacks, worry about the implications or
consequences of the attacks, and/or a significant change in behavior related to the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in panic disorder patients whose
diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under
CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period
of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and
reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating;
(3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6)
chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or
faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10)
fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills
or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in patients with panic disorder who responded
during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under
CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week placebo-controlled
trials of outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical
Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or
threatened death or serious injury, or threat to the physical integrity of self or others, and a response
which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the
traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or
dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event;
avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or
numbing of general responsiveness manifested as diminished interest in significant activities, estrangement
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from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic
arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired
concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are
present for at least a month and that they cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in patients with PTSD for up to 28 weeks following
24 weeks of open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the
physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-
term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD).
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled trials of
female outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of
PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability,
and persistent anger or irritability. Other features include decreased interest in activities, difficulty
concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms
associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight
gain. These symptoms occur regularly during the luteal phase and remit within a few days following
onset of menses; the disturbance markedly interferes with work or school or with usual social activities
and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical
mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been
systematically evaluated in controlled trials. Therefore, the physician who elects to use ZOLOFT for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of social anxiety disorder, also known as social phobia.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two placebo-
controlled trials of outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria
(see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent
fear of social or performance situations involving exposure to unfamiliar people or possible
scrutiny by others and by fears of acting in a humiliating or embarrassing way. Exposure to
the feared social situation almost always provokes anxiety and feared social or
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performance situations are avoided or else are endured with intense anxiety or distress. In
addition, patients recognize that the fear is excessive or unreasonable and the avoidance
and anticipatory anxiety of the feared situation is associated with functional impairment or
marked distress.
The efficacy of ZOLOFT in maintaining a response in patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a
placebo-controlled trial. Physicians who prescribe ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
Clinical Trials under CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see
WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content
of the concentrate.
WARNINGS
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT® (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an MAOI,
or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should
be allowed after stopping ZOLOFT before starting an MAOI.
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PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred in
approximately 0.4% of ZOLOFT® (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline for some
patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus
smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were
excluded from clinical studies during the product’s premarket testing. No seizures were observed
among approximately 3000 patients treated with ZOLOFT in the development program for major
depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age) exposed
during the development program for obsessive-compulsive disorder experienced seizures, representing
a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and
one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication.
Accordingly, ZOLOFT should be introduced with care in patients with a seizure disorder.
Suicide–The possibility of a suicide attempt is inherent in major depressive disorder and may persist
until significant remission occurs. Close supervision of high risk patients should accompany initial drug
therapy. Prescriptions for ZOLOFT should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Because of the well-established comorbidity between OCD, panic disorder, PTSD,
PMDD or social anxiety disorder and major depressive disorder, the same precautions
observed when treating patients with major depressive disorder should be observed when
treating patients with OCD, panic disorder, PTSD, PMDD or social anxiety disorder.
Weak Uricosuric Effect–ZOLOFT® (sertraline hydrochloride) is associated with a mean decrease in
serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with certain
concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients with diseases
or conditions that could affect metabolism or hemodynamic responses.
ZOLOFT has not been evaluated or used to any appreciable extent in patients with a recent history of
myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from
clinical studies during the product’s premarket testing. However, the electrocardiograms of 774 patients
who received ZOLOFT in double-blind trials were evaluated and the data indicate that ZOLOFT is not
associated with the development of significant ECG abnormalities.
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The
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15
effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
use of sertraline in patients with liver disease must be approached with caution. If sertraline is
administered to patients with liver impairment, a lower or less frequent dose should be used (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor route of
elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in
patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the
pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic
results, there is no need for dosage adjustment in patients with renal impairment (see CLINICAL
PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for Patients.)
Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible
when ZOLOFT was discontinued. Some cases were possibly due to the syndrome of inappropriate
antidiuretic hormone secretion. The majority of these occurrences have been in elderly individuals, some
in patients taking diuretics or who were otherwise volume depleted.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal results
from laboratory studies in patients taking ZOLOFT. While there have been reports of abnormal
bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT had a causative
role.
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe ZOLOFT:
Patients should be told that although ZOLOFT has not been shown to impair the ability of normal
subjects to perform tasks requiring complex motor and mental skills in laboratory experiments,
drugs that act upon the central nervous system may affect some individuals adversely. Therefore,
patients should be told that until they learn how they respond to ZOLOFT they should be careful
doing activities when they need to be alert, such as driving a car or operating machinery.
Patients should be told that although ZOLOFT has not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use
of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter (OTC)
drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC
product should be initiated cautiously according to the directions of use given for the OTC product.
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Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze may
appear after mixing; this is normal. Note that caution should be exercised for persons with latex
sensitivity, as the dropper dispenser contains dry natural rubber.
Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT® (sertraline hydrochloride)
to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a
shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may
result from displacement of protein bound ZOLOFT by other tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg)
before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or placebo, there was a
mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared to a 1% decrease
for placebo (p<0.02). The normalization of prothrombin time for the ZOLOFT group was delayed
compared to the placebo group. The clinical significance of this change is unknown. Accordingly,
prothrombin time should be carefully monitored when ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC
(50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of
these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered diazepam
before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or
placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group
compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23%
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increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the
placebo group (p<0.03). The clinical significance of these changes is unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not
significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation
of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to
steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was
not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has
not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses
higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to
the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide,
concomitant administration of ZOLOFT and pimozide should be contraindicated (see
CONTRAINDICATIONS).
The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically
evaluated. Consequently, caution is advised if the concomitant administration of ZOLOFT and such
drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other drugs
effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder,
posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to ZOLOFT.
Care and prudent medical judgment should be exercised when switching, particularly from long-acting
agents. The duration of an appropriate washout period which should intervene before switching from
one selective serotonin reuptake inhibitor (SSRI) to another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under
steady-state conditions. The results of these studies indicated that sertraline did not increase plasma
concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline’s extent
of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction
study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride
AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the
treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme
cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of
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co-administered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction
is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic
index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and
the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an
important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant
and the therapeutic index of the co-administered drug. There is variability among the drugs effective in
the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class.
Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently,
concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require lower doses than
usually prescribed for the other drug. Furthermore, whenever ZOLOFT is withdrawn from co-therapy,
an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs
Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS).
Sumatriptan–There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and
sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is
advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on the
degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in
the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA metabolism. Plasma
TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a
TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450 2D6 under
PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT
for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease
from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. ZOLOFT
administration did not noticeably change either the plasma protein binding or the apparent volume of
distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the
metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the
beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days
(including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal
clearance.
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Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as
determined by a small (5%) but statistically significant decrease in antipyrine half-life following
administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically
insignificant change in hepatic metabolism.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in
experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats
at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the
maximum recommended human dose (MRHD) on a mg/m2 basis. There was a dose-related increase of
liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m2
basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor
was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous
occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in
follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on
a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine
adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2
basis) compared to placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on the
following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic
aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and rabbits at
doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately
4 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There was no evidence of
teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period
of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the
MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m2 basis) in rabbits. When
female rats received sertraline during the last third of gestation and throughout lactation, there was an
increase in the number of stillborn pups and in the number of pups dying during the first 4 days after
birth. Pup body weights were also decreased during the first four days after birth. These effects
occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup
mortality was 10 mg/kg (0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was
shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.
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There are no adequate and well-controlled studies in pregnant women. ZOLOFT® (sertraline
hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its metabolites are
excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised
when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17 (see
Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of ZOLOFT in pediatric patients
with major depressive disorder, panic disorder, PTSD, PMDD or social anxiety disorder has not been
systematically evaluated.
The safety of ZOLOFT use in children and adolescents, ages 6-18, was evaluated in a 12-week,
multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible dose, 52 week
open extension study of 137 patients, ages 6-18, who had completed the initial 12-week, double-blind,
placebo-controlled study. ZOLOFT was administered at doses of either 25 mg/day (children, ages 6-
12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day
increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean
dose for completers was 157 mg/day. In the acute 12 week pediatric study and in the 52 week study,
ZOLOFT had an adverse event profile generally similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 18 years of age with
major depressive disorder and/or OCD and revealed similar drug exposures to those of adults when
plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL
PHARMACOLOGY).
More than 250 patients with major depressive disorder and/or OCD between 6 and 18 years of age
have received ZOLOFT in clinical trials. The adverse event profile observed in these patients was
generally similar to that observed in adult studies with ZOLOFT (see ADVERSE REACTIONS). As
with other SSRIs, decreased appetite and weight loss have been observed in association with the use of
ZOLOFT. Consequently, regular monitoring of weight and growth is recommended if treatment of a
child with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the
age of 6 have not been established.
The risks, if any, that may be associated with the use of ZOLOFT beyond 1 year in children and
adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the
evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from
clinical studies that were 12 to 52 weeks in duration and from the extrapolation of experience gained
with adult patients. In particular, there are no studies that directly evaluate the effects of long-term
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sertraline use on the growth, development, and maturation of children and adolescents. Although there is
no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth,
development or maturation, the absence of such findings is not compelling evidence of the absence of
the potential of sertraline to have adverse effects in chronic use.
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included 663
ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall
differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative
to those reported in younger subjects (see ADVERSE REACTIONS), and other reported experience
has not identified differences in safety patterns between the elderly and younger subjects. As with all
medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects
in placebo-controlled geriatric clinical studies of ZOLOFT in major depressive disorder. No overall
differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those
reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in placebo-
controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 1 and
2. Urinary tract infection was the only adverse event not appearing in Tables 1 and 2 and reported at an
incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant hyponatremia in
elderly patients (see Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over 4000 adult
subjects as of February 26, 1998. The conditions and duration of exposure to ZOLOFT varied greatly,
and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies,
uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and
studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using terminology
of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events without first grouping similar types of untoward
events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been used to
classify reported adverse events. The frequencies presented, therefore, represent the proportion of the
over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced a
treatment-emergent adverse event of the type cited on at least one occasion while receiving ZOLOFT.
An event was considered treatment-emergent if it occurred for the first time or worsened while receiving
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therapy following baseline evaluation. It is important to emphasize that events reported during therapy
were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict
the incidence of side effects in the course of usual medical practice where patient characteristics and
other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot
be compared with figures obtained from other clinical investigations involving different treatments, uses,
and investigators. The cited figures, however, do provide the prescribing physician with some basis for
estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the
population studied.
Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common
treatment-emergent adverse events associated with the use of ZOLOFT (incidence of at
least 5% for ZOLOFT and at least twice that for placebo within at least one of the
indications) for the treatment of adult patients with major depressive disorder/other*,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled
clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder,
PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in
the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to
150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual
cycle received doses of 50 to 100 mg/day. Table 2 enumerates treatment-emergent
adverse events that occurred in 2% or more of adult patients treated with ZOLOFT and
with incidence greater than placebo who participated in controlled clinical trials comparing
ZOLOFT with placebo in the treatment of major depressive disorder/other*, OCD, panic
disorder, PTSD, PMDD and social anxiety disorder. Table 2 provides combined data for
the pool of studies that are provided separately by indication in Table 1.
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TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS:
INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Centr. & Periph. Nerv.
System Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety
Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Centr. & Periph. Nerv.
System Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
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Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients in
PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 1
should be avoided.
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TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS:
INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety
Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Centr. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
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*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had an
incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT® (sertraline hydrochloride)
treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT in clinical trials) in
major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive disorder/other*;
N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205 social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
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Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment.
In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause
such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward
experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part
because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the
incidence of untoward sexual experience and performance cited in product labeling, are likely to
underestimate their actual incidence.
Table 4 below displays the incidence of sexual side effects reported by at least 2% of patients taking
ZOLOFT in placebo-controlled trials.
TABLE 4
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs,
physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In approximately N=250 pediatric patients treated
with ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies, as
shown in Tables 1 and 2. However, the following adverse events, not appearing in Tables 1 and 2, were
reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate in a
controlled trial (N=187): hyperkinesia, twitching, fever, malaise, purpura, weight decrease,
concentration impaired, manic reaction, emotional lability, thinking abnormal, and epistaxis.
Other Events Observed During the Premarketing Evaluation of ZOLOFT® (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during premarketing
assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those already listed in the
previous tables or elsewhere in labeling.
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In the tabulations that follow, a World Health Organization dictionary of terminology has been used to
classify reported adverse events. The frequencies presented, therefore, represent the proportion of the
over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced an event of the
type cited on at least one occasion while receiving ZOLOFT. All events are included except those
already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to
be uninformative and those for which a causal relationship to ZOLOFT treatment seemed remote. It is
important to emphasize that although the events reported occurred during treatment with ZOLOFT, they
were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to
the following definitions: frequent adverse events are those occurring on one or more occasions in at
least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare
events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also
described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural
dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia,
syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated
hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia,
hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup,
stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic
peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.
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General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis,
muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy,
abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated
depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism,
illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast
enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory
tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea,
bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual
field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention, dysuria,
nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and
SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with ZOLOFT®
(sertraline hydrochloride) administration. These hepatic enzyme elevations usually occurred within the
first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
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ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately 3%)
and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%)
of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive
disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT–Reports of adverse
events temporally associated with ZOLOFT that have been received since market introduction, that are
not listed above and that may have no causal relationship with the drug, include the following: acute renal
failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation
times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia
(including torsade de pointes-type arrhythmias), hypothyroidism, agranulocytosis, aplastic anemia and
pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, ,
galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal
symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin
reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity
and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical features
(which in the majority of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in
one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice,
abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT® (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized study
of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans, ZOLOFT
did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug
liking, that were observed with the other two drugs. Premarketing clinical experience with ZOLOFT did
not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. In animal studies
ZOLOFT does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any
CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and
follow such patients closely, observing them for signs of ZOLOFT misuse or abuse (e.g., development
of tolerance, incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone
or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal
outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include
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31
alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin
syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms
associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia,
nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and
subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride
alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or multiple
drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations,
hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome,
stupor and syncope.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if
needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug, forced
diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific
antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should
consider contacting a poison control center on the treatment of any overdose. Telephone numbers for
certified poison control centers are listed in the Physicians’ Desk Reference® (PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should be
administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–
ZOLOFT treatment should be initiated with a dose of 25 mg once daily. After one week,
the dose should be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major
depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were
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dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for the treatment of these indications. Consequently, a dose of 50 mg,
administered once daily, is recommended as the initial therapeutic dose. Patients not
responding to a 50 mg dose may benefit from dose increases up to a maximum of
200 mg/day. Given the 24 hour elimination half-life of ZOLOFT, dose changes should not
occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual
cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were dosed
in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle (see
Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a 50 mg/day dose
may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing
daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the
menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day
titration step for three days should be utilized at the beginning of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg once
daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were dosed in
a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for pediatric
patients (6-17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may
benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally
lower body weights compared to adults should be taken into consideration in advancing the dose, in
order to avoid excess dosing. Given the 24 hour elimination half-life of ZOLOFT, dose changes should
not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Hepatically Impaired Patients
The use of sertraline in patients with liver disease should be approached with caution. The effects of
sertraline in patients with moderate and severe hepatic impairment have not been studied. If sertraline is
administered to patients with liver impairment, a lower or less frequent dose should be used (see
CLINICAL PHARMACOLOGY and PRECAUTIONS).
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Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive disorder
require several months or longer of sustained pharmacologic therapy beyond response to the acute
episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant efficacy is
maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200
mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL PHARMACOLOGY). It is
not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose
needed to achieve an initial response. Patients should be periodically reassessed to determine the need
for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or longer of
sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of
ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks
following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be periodically
reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require
several months or longer of sustained pharmacological therapy beyond response to initial
treatment. Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social
anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of
treatment at a dose of 50-200 mg/day (see Clinical Trials under CLINICAL
PHARMACOLOGY). Dosage adjustments should be made to maintain patients on the
lowest effective dose and patients should be periodically reassessed to determine the need
for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and Panic
Disorder require several months or longer of sustained pharmacological therapy beyond response to
initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to 28 weeks in patients
with OCD and Panic Disorder who have responded while taking ZOLOFT during initial treatment
phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of
such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY). It is not
known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed
to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the
need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for more
than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women
commonly report that symptoms worsen with age until relieved by the onset of menopause, it is
reasonable to consider continuation of a responding patient. Dosage adjustments, which may include
changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal
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34
phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and
patients should be periodically reassessed to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should elapse
between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before taking,
use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4
oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix
ZOLOFT Oral Concentrate with anything other than the liquids listed. The dose should be taken
immediately after mixing. Do not mix in advance. At times, a slight haze may appear after mixing; this is
normal. Note that caution should be exercised for patients with latex sensitivity, as the dropper
dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content
of the concentrate.
HOW SUPPLIED
ZOLOFT® (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT® 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and on
the other side scored and engraved with 25 mg.
NDC 0049-4960-50
Bottles of 50
ZOLOFT® 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and on the
other side scored and engraved with 50 mg.
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT® 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 100 mg.
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35
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a menthol
scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol. It is
supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room
Temperature].
Rx only
2002 Pfizer Inc
D i s t r i b u t e d b y
Roerig
Division of Pfizer Inc, NY, NY 10017
69-4721-00-4.2
Revised December 2002
File: zoloft\SAD\AP\19839S45AP label.doc
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|
custom-source
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2025-02-12T13:46:01.945878
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020990s011lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 45}
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1
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a
child or adolescent must balance this risk with the clinical need. Patients who are started on
therapy should be observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings and Precautions:
Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant
drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD),
obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials
involving over 4400 patients) have revealed a greater risk of adverse events representing
suicidal thinking or behavior (suicidality) during the first few months of treatment in those
receiving antidepressants. The average risk of such events in patients receiving
antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
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2
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
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3
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to downregulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
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4
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
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resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
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Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
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The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
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combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. There has been a long-
standing concern that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal
thinking and behavior (suicidality) in short-term studies in children and adolescents with Major
Depressive Disorder (MDD) and other psychiatric disorders.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others)
in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials
involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal
behavior or thinking (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice
the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward
an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the
MDD trials, but there were signals of risk arising from some trials in other psychiatric indications
(obsessive-compulsive disorder and social anxiety disorder) as well. No suicides occurred in any
of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-
term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to
adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during
the initial few months of a course of drug therapy, or at times of dose changes, either increases
or decreases. Such observation would generally include at least weekly face-to-face contact
with patients or their family members or caregivers during the first 4 weeks of treatment, then
every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated
beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face
visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and
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suicidality, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to health care
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for ZOLOFT should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose. Families and caregivers of
adults being treated for depression should be similarly advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
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PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
Published case reports have documented the occurrence of bleeding episodes in patients treated
with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological
studies, both of the case-control and cohort design, have demonstrated an association between
use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. In two studies, concurrent use of a non-selective nonsteroidal anti-
inflammatory drug (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or
aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies
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focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites
may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding
associated with the concomitant use of ZOLOFT with non-selective NSAIDs (i.e., NSAIDs that
inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other drugs that affect
coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible
when ZOLOFT was discontinued. Some cases were possibly due to the syndrome of
inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in
elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide About Using
Antidepressants in Children and Teenagers is available for ZOLOFT. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be
given the opportunity to discuss the contents of the Medication Guide and to obtain answers
to any questions they may have. The complete text of the Medication Guide is reprinted at
the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to observe for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
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19
these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and non-selective
NSAIDs (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin,
or other drugs that affect coagulation since the combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk
of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
None.
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Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
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Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of Zoloft on valproate levels has not been evaluated in clinical trials. In the absence
of such data, it is recommended that plasma valproate levels be monitored following initiation of
Zoloft therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
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lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Sumatriptan–There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between the use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of a non-selective NSAID (i.e.,
NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the
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risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently
with ZOLOFT.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
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Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on postmarketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general
population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six-
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic in the context of antidepressant
therapy at the beginning of pregnancy, women who discontinued antidepressant medication
during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
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The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
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prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in
Tables 1 and 2 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant
hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
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experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution of drug and
nondrug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 2
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 2
provides combined data for the pool of studies that are provided separately by indication in
Table 1.
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TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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29
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 1
should be avoided.
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TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Centr. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
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difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 4 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 4
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 1 and 2,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
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Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
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35
hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms,
oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity
and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical
features (which in the majority of cases appeared to be reversible with discontinuation of
ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin,
hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
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36
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
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37
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
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38
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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39
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
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40
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT® Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only
LAB-0218-12.0
Revised July 2006
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41
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But
suicidal thoughts and actions can also be caused by depression, a serious medical condition that
is commonly treated with antidepressants. Thinking about killing yourself or trying to kill
yourself is called suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with
depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an
antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients
became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4
out of every 100 patients became suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in
her or his moods or actions, especially if the changes occur suddenly. Other important people in
your child’s life can help by paying attention as well (e.g., your child, brothers and sisters,
teachers, and other important people). The changes to look out for are listed in Section 3, on
what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
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42
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider’s advice about how often to come back
• More often if problems or questions arise (see Section 3)
You should call your child’s healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child’s healthcare provider right away if your child exhibits any of the following
signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses
can lead to suicide. In some children and teenagers, treatment with an antidepressant increases
suicidal thinking or actions. It is important to discuss all the risks of treating depression and also
the risks of not treating it. You and your child should discuss all treatment choices with your
healthcare provider, not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric
depression.
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43
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®).
Your healthcare provider may suggest other antidepressants based on the past experience of your
child or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with
antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the
particular drug he or she is prescribing. Also ask about drugs to avoid when taking an
antidepressant. Ask your healthcare provider or pharmacist where to find more information.
*Prozac® is a registered trademark of Eli Lilly and Company
*Zoloft® is a registered trademark of Pfizer Pharmaceuticals
*Anafranil® is a registered trademark of Mallinckrodt Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
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1
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,
synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral
concentrate must be diluted prior to administration (see PRECAUTIONS, Information for Patients
and DOSAGE AND ADMINISTRATION).
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2
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to downregulate brain norepinephrine receptors,
as has been observed with other drugs effective in the treatment of major depressive disorder.
Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to 200 mg
for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to
8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the
plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50
to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold
accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg
dose range. The single dose bioavailability of sertraline tablets is approximately equal to an
equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral
solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric
mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals
(CI) were within the range of 80-125% with the exception of the upper 90% CI limit for Cmax
which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied
in subjects administered a single dose with and without food. For the tablet, AUC was slightly
increased when drug was administered with food but the Cmax was 25% greater, while the time to
reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the
oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
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3
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old group
exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean
half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely attributable to
patients with lower body weights. No gender associated differences were observed. By
comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male,
11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC
(0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr. Relative to
the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower AUC
(0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data
suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights,
especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND
ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in
older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
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4
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects of
sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is a
minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate
to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each
group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21
days were not altered compared to age-matched volunteers (N=12) with no renal impairment.
Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see
PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2
was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Overall,
these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression Rating
Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not
readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis
of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of OCD
was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the
mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
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reduction of approximately 4 points on the YBOCS total score which was significantly greater than
the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the
mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater than
the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness on
the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children
and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at doses of
either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then titrated
over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for
completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this
study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s
Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving
sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score
which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and
gender effects on outcome did not suggest any differential responsiveness on the basis of age or
sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a
52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to continuation
of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation
due to relapse or insufficient clinical response. Response during the single-blind phase was
defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very
much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind
phase was defined as the following conditions being met (on three consecutive visits for 1 and 2,
and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20,
relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s
condition in the investigator’s judgment, to justify alternative treatment. Insufficient clinical
response indicated a worsening of the patient’s condition that resulted in study discontinuation, as
assessed by the investigator. Patients receiving continued ZOLOFT treatment experienced a
significantly lower rate of discontinuation due to relapse or insufficient clinical response over the
subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male
and female subjects.
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and on
the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference
between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was
approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack frequency
than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response
relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded
during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to continuation
of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due
to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-
I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase
was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2)
meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline.
Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of PTSD
was established in two multicenter placebo-controlled studies (Studies 1-2) of adult outpatients
who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was
12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had
secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day,
respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered
PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD
diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as
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well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance
symptoms. ZOLOFT was shown to be significantly more effective than placebo on change from
baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of
Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the
difference in response to treatment between patients receiving ZOLOFT and patients receiving
placebo was not statistically significant. One of these additional studies was conducted in patients
similar to those recruited for Studies 1 and 2, while the second additional study was conducted in
predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in these
trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this apparent
gender interaction is unknown at this time. There was insufficient information to determine the
effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a
24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-
I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment of
PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria
for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase
dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for
these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were
excluded from these trials; therefore, the efficacy of sertraline in combination with oral
contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes
assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments
included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression
Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
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In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed
in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for
completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual cycle was
significantly more effective than placebo on change from baseline to endpoint on the DRSP total
score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day in
the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of
menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to
100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder
of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT administered in
the late luteal phase of the menstrual cycle was significantly more effective than placebo on change
from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score
at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day) to
placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and by
(b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200 mg/day)
to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a
multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to
social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-
SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance
and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was shown to be statistically
significantly more effective than placebo as measured by the BSPS total score and fear, avoidance
and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more
responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There
was insufficient information to determine the effect of race or age on outcome.
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In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial
on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution of
placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase
in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or
study discontinuation due to lack of efficacy. Patients receiving ZOLOFT continuation treatment
experienced a statistically significantly lower relapse rate over this 24-week study than patients
randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT® (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the
DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following
8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled
trial. The usefulness of the drug in patients receiving ZOLOFT for extended periods should be
reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R;
i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly
interfere with social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive outpatients
having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or
DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
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intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during a
52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about the
implications or consequences of the attacks, and/or a significant change in behavior related to the
attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical
Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart
rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5)
feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling
dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization
(being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias
(numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to
use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or
threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
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exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on
exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability
to recall details of the event, and/or numbing of general responsiveness manifested as diminished
interest in significant activities, estrangement from others, restricted range of affect, or sense of
foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated
startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A
PTSD diagnosis requires that the symptoms are present for at least a month and that they cause
clinically significant distress or impairment in social, occupational, or other important areas of
functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28 weeks
following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial.
Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled trials
of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV
category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit
within a few days following onset of menses; the disturbance markedly interferes with work or
school or with usual social activities and relationships with others. In making the diagnosis, care
should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment
with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug
for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined
by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
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Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is
excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see
WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT® (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an MAOI,
or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should
be allowed after stopping ZOLOFT before starting an MAOI.
Clinical Worsening and Suicide Risk
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Patients with major depressive disorder, both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or
not they are taking antidepressant medications, and this risk may persist until significant remission
occurs. Although there has been a long-standing concern that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain patients, a causal
role for antidepressants in inducing such behaviors has not been established. Nevertheless,
patients being treated with antidepressants should be observed closely for clinical worsening
and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose
changes, either increases or decreases. Consideration should be given to changing the
therapeutic regimen, including possibly discontinuing the medication, in patients whose depression
is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of
the patient’s presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other
psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients
with major depressive disorder should be observed when treating patients with other psychiatric
and nonpsychiatric disorders.
The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility
(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, consideration
should be given to changing the therapeutic regimen, including possibly discontinuing the
medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the
need to monitor patients for the emergence of agitation, irritability, and the other symptoms
described above, as well as the emergence of suicidality, and to report such symptoms
immediately to health care providers. Prescriptions for ZOLOFT should be written for the
smallest quantity of tablets consistent with good patient management, in order to reduce the risk of
overdose.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as
is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
It should be noted that ZOLOFT is approved in the pediatric population only for obsessive
compulsive disorder.
A major depressive episode may be the initial presentation of bipolar disorder. It is generally
believed (though not established in controlled trials) that treating such an episode with an
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antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in
patients at risk for bipolar disorder. Whether any of the symptoms described above represent such
a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients
should be adequately screened to determine if they are at risk for bipolar disorder; such screening
should include a detailed psychiatric history, including a family history of suicide, bipolar
disorder, and depression. It should be noted that ZOLOFT is not approved for use in treating
bipolar depression.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred in
approximately 0.4% of ZOLOFT® (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline for
some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss,
versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for
weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were
excluded from clinical studies during the product’s premarket testing. No seizures were observed
among approximately 3000 patients treated with ZOLOFT in the development program for major
depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age)
exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation
of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability,
agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations),
anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these
events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment,
then resuming the previously prescribed dose may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
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Published case reports have documented the occurrence of bleeding episodes in patients treated
with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological
studies, both of the case-control and cohort design, have demonstrated an association between use
of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. In two studies, concurrent use of a non-selective nonsteroidal anti-
inflammatory drug (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or
aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies
focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites
may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding
associated with the concomitant use of ZOLOFT with non-selective NSAIDs (i.e., NSAIDs that
inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other drugs that affect
coagulation.
Weak Uricosuric Effect–ZOLOFT® (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric
effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was
evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV
diagnosis of major depressive disorder and recent history of myocardial infarction or unstable
angina requiring hospitalization. Exclusions from this trial included, among others, patients with
uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index
event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically
significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days post-
MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on
the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular
events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia,
bradycardia, and changes in BP), and major cardiovascular events involving death or requiring
hospitalization (for MI, CHF, stroke, or angina).
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ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor route
of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that
in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the
pharmacokinetics and protein binding are unaffected by renal disease. Based on the
pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment
(see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible
when ZOLOFT was discontinued. Some cases were possibly due to the syndrome of inappropriate
antidiuretic hormone secretion. The majority of these occurrences have been in elderly
individuals, some in patients taking diuretics or who were otherwise volume depleted.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
ZOLOFT:
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to ZOLOFT
they should be careful doing activities when they need to be alert, such as driving a car or
operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and non-selective NSAIDs
(i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other
drugs that affect coagulation since the combined use of psychotropic drugs that interfere with
serotonin reuptake and these agents has been associated with an increased risk of bleeding.
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Patients should be told that although ZOLOFT has not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant
use of ZOLOFT and alcohol is not advised.
Patients and their families should be encouraged to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, worsening of depression, and suicidal ideation,
especially early during antidepressant treatment. Such symptoms should be reported to the
patient’s physician, especially if they are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any
OTC product should be initiated cautiously according to the directions of use given for the
OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just
before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids
listed. The dose should be taken immediately after mixing. Do not mix in advance. At times, a
slight haze may appear after mixing; this is normal. Note that caution should be exercised for
persons with latex sensitivity, as the dropper dispenser contains dry natural rubber.
Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT® (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or placebo,
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there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared
to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the ZOLOFT
group was delayed compared to the placebo group. The clinical significance of this change is
unknown. Accordingly, prothrombin time should be carefully monitored when ZOLOFT therapy is
initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC
(50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance
of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered diazepam
before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or
placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT
group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was
a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a 20%
decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did
not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax of
about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due
to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT and
pimozide should be contraindicated (see CONTRAINDICATIONS).
The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically
evaluated. Consequently, caution is advised if the concomitant administration of ZOLOFT and such
drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other drugs
effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic
disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which should
intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has
not been established.
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Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not increase
plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that
sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.
Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the
metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma
concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs for which
this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which
have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment
of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The
extent to which this interaction is an important clinical problem depends on the extent of the
inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug.
There is variability among the drugs effective in the treatment of major depressive disorder in the
extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less
prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has
the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug
metabolized by P450 2D6 with ZOLOFT may require lower doses than usually prescribed for the
other drug. Furthermore, whenever ZOLOFT is withdrawn from co-therapy, an increased dose of
the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the
Treatment of Major Depressive Disorder under PRECAUTIONS).
Sumatriptan–There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram,
fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of
the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant
16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg
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dose. ZOLOFT administration did not noticeably change either the plasma protein binding or the
apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to
a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide
clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the
beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days
(including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal
clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between the use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of a non-selective NSAID (i.e.,
NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the risk
of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with
ZOLOFT.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in
experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
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Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans
rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the
maximum recommended human dose (MRHD) on a mg/m2 basis. There was a dose-related
increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the
MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving
the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have
a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to
humans. There was an increase in follicular adenomas of the thyroid in female rats receiving
sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid
hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at
10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect
was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There
was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given
sertraline during the period of organogenesis, delayed ossification was observed in fetuses at
doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in the
number of pups dying during the first 4 days after birth. Pup body weights were also decreased
during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the
MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the
MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure
to sertraline. The clinical significance of these effects is unknown. There are no adequate and
well-controlled studies in pregnant women. ZOLOFT® (sertraline hydrochloride) should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on postmarketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting,
hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant
crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or,
possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical
picture is consistent with serotonin syndrome (see WARNINGS).
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When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION).
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its metabolites
are excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of ZOLOFT in pediatric
patients with major depressive disorder, panic disorder, PTSD, PMDD or social anxiety disorder
has not been established.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon
clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week pediatric
study and in the 52 week study, ZOLOFT had an adverse event profile generally similar to that
observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age
with major depressive disorder or OCD and revealed similar drug exposures to those of adults
when plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL
PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse event
profile observed in these patients was generally similar to that observed in adult studies with
ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and weight
loss have been observed in association with the use of ZOLOFT. In a pooled analysis of two 10-
week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major
depressive disorder (n=373), there was a difference in weight change between sertraline and
placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in both
cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At
baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At
baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There
was a bigger difference between sertraline and placebo in the proportion of outliers for clinically
important weight loss in children than in adolescents. For children, about 7% had a weight loss >
7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a
weight loss > 7% of body weight compared to about 1% of the placebo patients. A subset of these
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patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were
continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of
approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first
exposure to sertraline during the open-label extension study, similar to mean weight loss observed
among sertralinetreated subjects during the first eight weeks of the randomized controlled trials.
The subjects continuing in the open label study began gaining weight compared to baseline by
week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment
(10 weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight gain that was
similar to that expected using data from age-adjusted peers. Regular monitoring of weight and
growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long
term. Safety and effectiveness in pediatric patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest that
sertraline possesses a capacity to adversely affect growth, development or maturation, the absence
of such findings is not compelling evidence of the absence of the potential of sertraline to have
adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall
differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects
relative to those reported in younger subjects (see ADVERSE REACTIONS), and other reported
experience has not identified differences in safety patterns between the elderly and younger
subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled
out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in major
depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that shown
in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in Tables 1 and
2 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-
controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant
hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to ZOLOFT
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varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and
double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-
dose and titration studies, and studies for multiple indications, including major depressive
disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time or
worsened while receiving therapy following baseline evaluation. It is important to emphasize that
events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the
cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution of drug and nondrug
factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the treatment
of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive
disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of
50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle
received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of
the menstrual cycle received doses of 50 to 100 mg/day. Table 2 enumerates treatment-emergent
adverse events that occurred in 2% or more of adult patients treated with ZOLOFT and with
incidence greater than placebo who participated in controlled clinical trials comparing ZOLOFT
with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder. Table 2 provides combined data for the pool of studies that
are provided separately by indication in Table 1.
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25
TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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26
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male
patients in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table
1 should be avoided.
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TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety
Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Centr. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT® (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT in
clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorde
r
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose
Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
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severity of untoward experiences involving sexual desire, performance and satisfaction are
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 4 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 4
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 1 and 2,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence, aggressive
reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT® (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal relationship
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to ZOLOFT treatment seemed remote. It is important to emphasize that although the events reported
occurred during treatment with ZOLOFT, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or more
occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to
1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
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Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy,
abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated
depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and
SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT® (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
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interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms,
oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and
other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical features
(which in the majority of cases appeared to be reversible with discontinuation of ZOLOFT)
occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly,
hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT® (sertraline hydrochloride) is not a controlled substance.
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Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in
fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to
include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence
and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common
signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were
somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation,
serotonin syndrome, stupor and syncope.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug, forced
diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No
specific antidotes for sertraline are known.
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In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should be
administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be
increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of
50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the treatment
of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as
the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose
increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of ZOLOFT,
dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle
(see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a 50
mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150
mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the
luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase
dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal
phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
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35
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children
with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response to
the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of up
to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for
maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments should
be made to maintain patients on the lowest effective dose and patients should be periodically
reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and Panic
Disorder require several months or longer of sustained pharmacological therapy beyond response
to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to 28 weeks in
patients with OCD and Panic Disorder who have responded while taking ZOLOFT during initial
treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has
demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However,
as women commonly report that symptoms worsen with age until relieved by the onset of
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36
menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments,
which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle
versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the
lowest effective dosage and patients should be periodically reassessed to determine the need for
continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should elapse
between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
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37
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and
mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY.
Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The dose should
be taken immediately after mixing. Do not mix in advance. At times, a slight haze may appear after
mixing; this is normal. Note that caution should be exercised for patients with latex sensitivity, as
the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT® (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT® 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-50
Bottles of 50
ZOLOFT® 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT® 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
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38
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room
Temperature].
Rx only
2004 Pfizer Inc
Distributed by
Roerig
Division of Pfizer Inc, NY, NY 10017
LAB-0218-5.2.1
Revised July 2004
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|
custom-source
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2025-02-12T13:46:02.562277
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19839s047,050,20990s013,017lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 50}
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1
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk
with the clinical need. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction in
risk with antidepressants compared to placebo in adults aged 65 and older. Depression and
certain other psychiatric disorders are themselves associated with increases in the risk of
suicide. Patients of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening
and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
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2
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
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3
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
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4
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
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5
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
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Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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8
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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9
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
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The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
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Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of
9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in
adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable
variation in risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These risk differences
(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided
in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
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It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
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Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated
(see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with
Monoamine Oxidase Inhibitors.)
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome
may occur in treatment with SNRIs and SSRIs, including Zoloft, particularly with concomitant
use of serotonergic drugs (including triptans) and with drugs which impair metabolism of
serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a 5-hydroxytryptamine
receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases (see PRECAUTIONS – Drug
Interactions).
The concomitant use of SNRIs and SSRIs, including Zoloft, with serotonin precursors (such as
tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions).
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
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Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including Zoloft, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other
anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and
cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Zoloft and NSAIDs, aspirin, or other drugs that affect coagulation.
Published case reports have documented the occurrence of bleeding episodes in patients treated
with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological
studies, both of the case-control and cohort design, have demonstrated an association between
use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. In two studies, concurrent use of a non-selective nonsteroidal anti-
inflammatory drug (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or
aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies
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focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites
may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding
associated with the concomitant use of ZOLOFT with non-selective NSAIDs (i.e., NSAIDs that
inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other drugs that affect
coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including ZOLOFT. In
many cases, this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L
have been reported. Elderly patients may be at greater risk of developing hyponatremia with
SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be
at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT should be considered in
patients with symptomatic hyponatremia and appropriate medical intervention should be
instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions:
is available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
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Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use
of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of Zoloft and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be cautioned about the concomitant use of ZOLOFT and non-selective
NSAIDs (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin,
or other drugs that affect coagulation since the combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk
of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
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Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
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CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of Zoloft on valproate levels has not been evaluated in clinical trials. In the absence
of such data, it is recommended that plasma valproate levels be monitored following initiation of
Zoloft therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
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Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including Zoloft,
and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including
Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome). The concomitant
use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS
– Drug Interactions).
Triptans: There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including Zoloft,
with a triptan is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
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(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID
or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when Zoloft is initiated or
discontinued.
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
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25
the case-control and cohort design that have demonstrated an association between the use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of a non-selective NSAID (i.e.,
NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the
risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently
with ZOLOFT.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
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utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on post marketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general
population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six-
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic in the context of antidepressant
therapy at the beginning of pregnancy, women who discontinued antidepressant medication
during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
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were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
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The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 21 and 32. Urinary tract infection was the only adverse event not appearing in
Tables 21 and 32 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
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In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 21 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 32
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 32
provides combined data for the pool of studies that are provided separately by indication in
Table 21.
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TABLE 21
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table
21 should be avoided.
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TABLE 32
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 43 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 43
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
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difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 54 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 54
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 21 and
32, were reported at an incidence of at least 2% and occurred at a rate of at least twice the
placebo rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
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Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
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hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms,
oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity
and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical
features (which in the majority of cases appeared to be reversible with discontinuation of
ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin,
hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
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Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
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during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
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Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
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42
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT® Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only
LAB-0218-18.07.0
Revised January 2008August 2007
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43
Medication Guide
Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal
Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression, and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar illness
(also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started
or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
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44
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating
it. Patients and their families or other caregivers should discuss all treatment choices
with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about
the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show the
healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use
in children. Talk with your child’s healthcare provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
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|
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2025-02-12T13:46:03.126528
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019839s068,020990s031lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 68}
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1
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a
child or adolescent must balance this risk with the clinical need. Patients who are started on
therapy should be observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings and Precautions:
Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant
drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD),
obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials
involving over 4400 patients) have revealed a greater risk of adverse events representing
suicidal thinking or behavior (suicidality) during the first few months of treatment in those
receiving antidepressants. The average risk of such events in patients receiving
antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
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2
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
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CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to downregulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
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4
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
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5
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
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Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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8
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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9
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT® (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
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The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT® (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
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combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. There has been a long-
standing concern that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal
thinking and behavior (suicidality) in short-term studies in children and adolescents with Major
Depressive Disorder (MDD) and other psychiatric disorders.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others)
in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials
involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal
behavior or thinking (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice
the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward
an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the
MDD trials, but there were signals of risk arising from some trials in other psychiatric indications
(obsessive-compulsive disorder and social anxiety disorder) as well. No suicides occurred in any
of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-
term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to
adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during
the initial few months of a course of drug therapy, or at times of dose changes, either increases
or decreases. Such observation would generally include at least weekly face-to-face contact
with patients or their family members or caregivers during the first 4 weeks of treatment, then
every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated
beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face
visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and
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suicidality, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to health care
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for ZOLOFT should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose. Families and caregivers of
adults being treated for depression should be similarly advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
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PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT® (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
Published case reports have documented the occurrence of bleeding episodes in patients treated
with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological
studies, both of the case-control and cohort design, have demonstrated an association between
use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. In two studies, concurrent use of a non-selective nonsteroidal anti-
inflammatory drug (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or
aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies
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focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites
may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding
associated with the concomitant use of ZOLOFT with non-selective NSAIDs (i.e., NSAIDs that
inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other drugs that affect
coagulation.
Weak Uricosuric Effect–ZOLOFT® (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible
when ZOLOFT was discontinued. Some cases were possibly due to the syndrome of
inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in
elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide About Using
Antidepressants in Children and Teenagers is available for ZOLOFT. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be
given the opportunity to discuss the contents of the Medication Guide and to obtain answers
to any questions they may have. The complete text of the Medication Guide is reprinted at
the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to observe for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
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these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and non-selective
NSAIDs (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin,
or other drugs that affect coagulation since the combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk
of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
None.
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Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT® (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
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The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Sumatriptan–There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
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citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between the use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of a non-selective NSAID (i.e.,
NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the
risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently
with ZOLOFT.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
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Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT® (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on postmarketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
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vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION).
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
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and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in
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Tables 1 and 2 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant
hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution of drug and
nondrug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 2
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
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treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 2
provides combined data for the pool of studies that are provided separately by indication in
Table 1.
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TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Centr. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 1
should be avoided.
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TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Centr. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
31
Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT® (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
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32
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 4 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 4
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 1 and 2,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT® (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
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Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT® (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
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hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms,
oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity
and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical
features (which in the majority of cases appeared to be reversible with discontinuation of
ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin,
hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT® (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
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Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
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during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
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Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT® (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT® 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 25 mg.
NDC 0049-4960-50
Bottles of 50
ZOLOFT® 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
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40
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT® 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only
2005 Pfizer Inc
Distributed by
Roerig
Division of Pfizer Inc, NY, NY 10017
LAB-0218-7.0
Revised February 2005
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41
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But
suicidal thoughts and actions can also be caused by depression, a serious medical condition that
is commonly treated with antidepressants. Thinking about killing yourself or trying to kill
yourself is called suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with
depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an
antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients
became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4
out of every 100 patients became suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in
her or his moods or actions, especially if the changes occur suddenly. Other important people in
your child’s life can help by paying attention as well (e.g., your child, brothers and sisters,
teachers, and other important people). The changes to look out for are listed in Section 3, on
what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
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42
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider’s advice about how often to come back
• More often if problems or questions arise (see Section 3)
You should call your child’s healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child’s healthcare provider right away if your child exhibits any of the following
signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without fist talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses
can lead to suicide. In some children and teenagers, treatment with an antidepressant increases
suicidal thinking or actions. It is important to discuss all the risks of treating depression and also
the risks of not treating it. You and your child should discuss all treatment choices with your
healthcare provider, not just the use of antidepressants.
Other side effects can occur with antdepressants (see section below).
Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric
depression.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®).
Your healthcare provider may suggest other antidepressants based on the past experience of your
child or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with
antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the
particular drug he or she is prescribing. Also ask about drugs to avoid when taking an
antidepressant. Ask your healthcare provider or pharmacist where to find more information.
*Prozac® is a registered trademark of Eli Lilly and Company
*Zoloft® is a registered trademark of Pfizer Pharmaceuticals
*Anafranil® is a registered trademark of Mallinckrodt Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:03.161060
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11,758
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ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk
with the clinical need. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction in
risk with antidepressants compared to placebo in adults aged 65 and older. Depression and
certain other psychiatric disorders are themselves associated with increases in the risk of
suicide. Patients of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening
and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
1
Struct ural
Fo
rmula
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
2
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
3
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
4
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
5
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
6
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
7
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
8
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
9
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
10
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
11
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
12
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
13
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of
9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in
adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable
variation in risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These risk differences
(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided
in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
14
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
15
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated
(see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with
Monoamine Oxidase Inhibitors.)
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including
Zoloft treatment, but particularly with concomitant use of serotonergic drugs (including triptans)
with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or
other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most
severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status
changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like
signs and symptoms.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Zoloft with a 5-hydroxytryptamine receptor agonist (triptan) is
clinically warranted, careful observation of the patient is advised, particularly during treatment
initiation and dose increases.
The concomitant use of Zoloft with serotonin precursors (such as tryptophan) is not
recommended.
Treatment with Zoloft and any concomitant serotonergic or antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated.
16
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including Zoloft, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other
anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and
cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
17
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Zoloft and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
18
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including ZOLOFT. In
many cases, this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L
have been reported. Elderly patients may be at greater risk of developing hyponatremia with
SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be
at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT should be considered in
patients with symptomatic hyponatremia and appropriate medical intervention should be
instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions:
is available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
19
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use
of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of Zoloft and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
20
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
21
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of Zoloft on valproate levels has not been evaluated in clinical trials. In the absence
of such data, it is recommended that plasma valproate levels be monitored following initiation of
Zoloft therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
22
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including Zoloft,
and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including
Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome). The concomitant
use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS
– Drug Interactions).
Triptans: There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including Zoloft,
with a triptan is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
23
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID
or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when Zoloft is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
24
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on post marketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general
25
population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic in the context of antidepressant
therapy at the beginning of pregnancy, women who discontinued antidepressant medication
during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
26
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
27
663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
28
the prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
29
TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
30
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
31
TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
32
Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
33
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
34
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
35
Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea,
36
hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis,
pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-
Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports
of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be
reversible with discontinuation of ZOLOFT) occurring in one or more patients include: elevated
enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver
failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
37
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
38
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
39
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
40
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
41
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT® Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only Pfizer logo
LAB-0218-19.0
Revised January 2009
42
Medication Guide
Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal
Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression, and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar illness
(also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started
or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
43
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating
it. Patients and their families or other caregivers should discuss all treatment choices
with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about
the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show the
healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use
in children. Talk with your child’s healthcare provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
Revised October 2008
44
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custom-source
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2025-02-12T13:46:03.536800
|
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11,759
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ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk
with the clinical need. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction in
risk with antidepressants compared to placebo in adults aged 65 and older. Depression and
certain other psychiatric disorders are themselves associated with increases in the risk of
suicide. Patients of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening
and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
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hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
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resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
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Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
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The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of
9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in
adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable
variation in risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These risk differences
(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided
in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated
(see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with
Monoamine Oxidase Inhibitors.)
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including
Zoloft treatment, but particularly with concomitant use of serotonergic drugs (including triptans
and fentanyl) with drugs which impair metabolism of serotonin (including MAOIs), or with
antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin
syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes
hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs,
and mental status changes. Patients should be monitored for the emergence of serotonin
syndrome or NMS-like signs and symptoms.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Zoloft with a 5-hydroxytryptamine receptor agonist (triptan) is
clinically warranted, careful observation of the patient is advised, particularly during treatment
initiation and dose increases.
The concomitant use of Zoloft with serotonin precursors (such as tryptophan) is not
recommended.
Treatment with Zoloft and any concomitant serotonergic or antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated.
Co-administration of Zoloft with other drugs which enhance the effects of serotonergic
neurotransmission, such as tryptophan, fenfluramine, fentanyl, 5-HT agonists, or the herbal medicine
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
St. John’s Wort (hypericum perforatum) should be undertaken with caution and avoided whenever
possible due to the potential for pharmacodynamic interaction.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including Zoloft, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other
anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and
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cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Zoloft and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including ZOLOFT. In
many cases, this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L
have been reported. Elderly patients may be at greater risk of developing hyponatremia with
SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be
at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT should be considered in
patients with symptomatic hyponatremia and appropriate medical intervention should be
instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions:
is available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
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ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use
of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of Zoloft and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
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For current labeling information, please visit https://www.fda.gov/drugsatfda
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in
patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive
test results may be expected for several days following discontinuation of sertraline therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline
from benzodiazepines.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
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Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of Zoloft on valproate levels has not been evaluated in clinical trials. In the absence
of such data, it is recommended that plasma valproate levels be monitored following initiation of
Zoloft therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including Zoloft,
and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including
Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome). The concomitant
use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS
– Drug Interactions).
Triptans: There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including Zoloft,
with a triptan is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
23
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need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID
or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when Zoloft is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
24
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dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on post marketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general
25
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For current labeling information, please visit https://www.fda.gov/drugsatfda
population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six-
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic in the context of antidepressant
therapy at the beginning of pregnancy, women who discontinued antidepressant medication
during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
26
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Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
27
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663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
28
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the prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
29
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TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
30
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
31
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TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
32
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
33
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difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
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Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, , hyperglycemia, galactorrhea,
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hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis,
pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-
Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports
of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be
reversible with discontinuation of ZOLOFT) occurring in one or more patients include: elevated
enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver
failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
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Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
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during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
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Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
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NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT® Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only
LAB-0218-19.0
Revised August 2011
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43
Medication Guide
ZOLOFT (ZOH-loft)
(sertraline hydrochloride)
(Tablets and Oral Concentrate (solution))
Read the Medication Guide that comes with ZOLOFT before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there
is something you do not understand or want to learn more about.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is the most important information I should know about ZOLOFT?
ZOLOFT and other antidepressant medicines may cause serious side effects, including:
1. Suicidal thoughts or actions:
•
ZOLOFT and other antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, or young adults within the first few months of treatment or when the dose is
changed.
•
Depression or other serious mental illnesses are the most important causes of suicidal thoughts or
actions.
•
Watch for these changes and call your healthcare provider right away if you notice:
•
New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
•
Pay particular attention to such changes when ZOLOFT is started or when the dose is changed.
Keep all follow-up visits with your healthcare provider and call between visits if you are worried
about symptoms.
Call your healthcare provider right away if you have any of the following symptoms, or call 911
if an emergency, especially if they are new, worse, or worry you:
•
attempts to commit suicide
•
acting on dangerous impulses
•
acting aggressive or violent
•
thoughts about suicide or dying
•
new or worse depression
•
new or worse anxiety or panic attacks
•
feeling agitated, restless, angry or irritable
•
trouble sleeping
•
an increase in activity or talking more than what is normal for you
•
other unusual changes in behavior or mood
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if
an emergency. ZOLOFT may be associated with these serious side effects:
2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be
life-threatening and may include:
•
agitation, hallucinations, coma or other changes in mental status
•
coordination problems or muscle twitching (overactive reflexes)
•
racing heartbeat, high or low blood pressure
•
sweating or fever
•
nausea, vomiting, or diarrhea
•
muscle rigidity
3. Severe allergic reactions:
•
trouble breathing
•
swelling of the face, tongue, eyes or mouth
•
rash, itchy welts (hives) or blisters, alone or with fever or joint pain
4. Abnormal bleeding: ZOLOFT and other antidepressant medicines may increase your risk of bleeding
or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal
anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.
5. Seizures or convulsions
6. Manic episodes:
•
greatly increased energy
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•
severe trouble sleeping
•
racing thoughts
•
reckless behavior
•
unusually grand ideas
•
excessive happiness or irritability
•
talking more or faster than usual
7. Changes in appetite or weight. Children and adolescents should have height and weight monitored
during treatment.
8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may
include:
•
headache
•
weakness or feeling unsteady
•
confusion, problems concentrating or thinking or memory problems
Do not stop ZOLOFT without first talking to your healthcare provider. Stopping ZOLOFT too
quickly may cause serious symptoms including:
•
anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
•
headache, sweating, nausea, dizziness
•
electric shock-like sensations, shaking, confusion
What is ZOLOFT?
ZOLOFT is a prescription medicine used to treat depression. It is important to talk with your healthcare
provider about the risks of treating depression and also the risks of not treating it. You should discuss all
treatment choices with your healthcare provider. ZOLOFT is also used to treat:
•
Major Depressive Disorder (MDD)
•
Obsessive Compulsive Disorder (OCD)
•
Panic Disorder
•
Posttraumatic Stress Disorder (PTSD)
•
Social Anxiety Disorder
•
Premenstrual Dysphoric Disorder (PMDD)
Talk to your healthcare provider if you do not think that your condition is getting better with ZOLOFT
treatment.
Who should not take ZOLOFT?
Do not take ZOLOFT if you:
•
are allergic to sertraline or any of the ingredients in ZOLOFT. See the end of this Medication Guide
for a complete list of ingredients in ZOLOFT.
•
take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart
problems.
•
take Antabuse® (disulfiram) (if you are taking the liquid form of ZOLOFT) due to the alcohol
content.
•
take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are
not sure if you take an MAOI, including the antibiotic linezolid.
•
Do not take an MAOI within 2 weeks of stopping ZOLOFT.
•
Do not start ZOLOFT if you stopped taking an MAOI in the last 2 weeks.
People who take ZOLOFT close in time to an MAOI may have serious or even life-threatening
side effects. Get medical help right away if you have any of these symptoms:
•
high fever
•
uncontrolled muscle spasms
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•
stiff muscles
•
rapid changes in heart rate or blood pressure
•
confusion
•
loss of consciousness (pass out)
What should I tell my healthcare provider before taking ZOLOFT? Ask if you are not sure.
Before starting ZOLOFT, tell your healthcare provider if you:
•
Are taking certain drugs such as:
•
Medicines used to treat migraine headaches such as:
o triptans
•
Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:
o tricyclic antidepressants
o lithium
o diazepam
o SSRIs
o SNRIs
o antipsychotic drugs
o valproate
•
Medicines used to treat seizures such as:
o phenytoin
•
Medicines used to treat pain such as:
o tramadol
•
Medicines used to thin your blood such as:
o warfarin
•
Medicines used to control your heartbeat such as :
o propafenone
o flecainide
o digitoxin
•
Medicines used to treat type II diabetes such as:
o tolbutamide
•
Cimetidine used to treat heartburn
•
Over-the-counter medicines or supplements such as:
o Aspirin or other NSAIDs
o tryptophan
o St. John’s Wort
•
have liver problems
•
have kidney problems.
•
have heart problems
•
have or had seizures or convulsions
•
have bipolar disorder or mania
•
have low sodium levels in your blood
•
have a history of a stroke
•
have high blood pressure
•
have or had bleeding problems
•
are pregnant or plan to become pregnant. It is not known if ZOLOFT will harm your unborn baby.
Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
•
are breast-feeding or plan to breast-feed. Some ZOLOFT may pass into your breast milk. Talk to your
healthcare provider about the best way to feed your baby while taking ZOLOFT.
46
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all the medicines that you take, including prescription and non-
prescription medicines, vitamins, and herbal supplements. ZOLOFT and some medicines may interact
with each other, may not work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell you if it is safe to take ZOLOFT with your other
medicines. Do not start or stop any medicine while taking ZOLOFT without talking to your healthcare
provider first.
If you take ZOLOFT, you should not take any other medicines that contain sertraline (sertraline HCl,
sertraline hydrochloride, etc.).
How should I take ZOLOFT?
•
Take ZOLOFT exactly as prescribed. Your healthcare provider may need to change the dose of
ZOLOFT until it is the right dose for you.
•
ZOLOFT Tablets may be taken with or without food.
•
ZOLOFT Oral Concentrate must be diluted before use:
o Follow the instructions carefully
o When diluting ZOLOFT Oral Concentrate, use ONLY water, ginger ale, lemon/lime soda,
lemonade, or orange juice.
o If you are sensitive to latex, be careful when using the dropper to dispense the Oral
Concentrate.
•
If you miss a dose of ZOLOFT, take the missed dose as soon as you remember. If it is almost time for
the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses
of ZOLOFT at the same time.
•
If you take too much ZOLOFT, call your healthcare provider or poison control center right away, or
get emergency treatment.
What should I avoid while taking ZOLOFT?
ZOLOFT can cause sleepiness or may affect your ability to make decisions, think clearly, or react
quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know
how ZOLOFT affects you. Do not drink alcohol while using ZOLOFT.
What are the possible side effects of ZOLOFT?
ZOLOFT may cause serious side effects, including:
• See “What is the most important information I should know about ZOLOFT?”
•
Feeling anxious or trouble sleeping
Common possible side effects in people who take ZOLOFT include:
• nausea, loss of appetite, diarrhea or indigestion
• change in sleep habits including increased sleepiness or insomnia
• increased sweating
• sexual problems including decreased libido and ejaculation failure
• tremor or shaking
• feeling tired or fatigued
• agitation
Other side effects in children and adolescents include:
• abnormal increase in muscle movement or agitation
• nose bleed
• urinating more often
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48
• urinary incontinence
• aggressive reaction
• heavy menstrual periods
• possible slowed growth rate and weight change. Your child’s height and weight should be
monitored during treatment with ZOLOFT.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These
are not all the possible side effects of ZOLOFT. For more information, ask your healthcare provider or
pharmacist.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY
REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.
How should I store ZOLOFT?
•
Store ZOLOFT at room temperature, between 59°F and 86°F (15°C to 30°C).
•
Keep ZOLOFT bottle closed tightly.
Keep ZOLOFT and all medicines out of the reach of children.
General information about ZOLOFT
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use ZOLOFT for a condition for which it was not prescribed. Do not give ZOLOFT to other people, even
if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about ZOLOFT. If you would like
more information, talk with your healthcare provider. You may ask your healthcare provider or
pharmacist for information about ZOLOFT that is written for healthcare professionals.
For more information about ZOLOFT call 1-800-438-1985 or go to www.pfizer.com
What are the ingredients in ZOLOFT?
Active ingredient: sertraline hydrochloride
Inactive ingredients
•
Tablets: dibasic calcium phosphate dihydrate, D&C Yellow #10 aluminum lake (in 25 mg tablet),
FD&C Blue #1 aluminum lake (in 25 mg tablet), FD&C Red #40 aluminum lake (in 25 mg tablet),
FD&C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,
synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide
•
Oral concentration: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT)
Revised August 2011
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:04.293234
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019839s072s075s076,020990s033s036s037lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 75}
|
11,760
|
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk
with the clinical need. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction in
risk with antidepressants compared to placebo in adults aged 65 and older. Depression and
certain other psychiatric disorders are themselves associated with increases in the risk of
suicide. Patients of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. Zoloft is not approved for use in pediatric patients except
for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening
and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural
formula:
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NHCH3 HCl
Cl
Cl
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
2
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CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
3
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hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
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resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
6
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Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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For current labeling information, please visit https://www.fda.gov/drugsatfda
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24-
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re-
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
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Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of
9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in
adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable
variation in risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These risk differences
(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided
in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of serious sometimes fatal reactions have been reported in patients receiving
ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in
combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction
between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that include
confusion, irritability, and extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued an SSRI and
have been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, ZOLOFT should not be used in combination with an
MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated
(see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with
Monoamine Oxidase Inhibitors.)
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including
Zoloft treatment, but particularly with concomitant use of serotonergic drugs (including triptans
and fentanyl) with drugs which impair metabolism of serotonin (including MAOIs), or with
antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin
syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes
hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs,
and mental status changes. Patients should be monitored for the emergence of serotonin
syndrome or NMS-like signs and symptoms.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Zoloft with a 5-hydroxytryptamine receptor agonist (triptan) is
clinically warranted, careful observation of the patient is advised, particularly during treatment
initiation and dose increases.
The concomitant use of Zoloft with serotonin precursors (such as tryptophan) is not
recommended.
Treatment with Zoloft and any concomitant serotonergic or antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated.
Co-administration of Zoloft with other drugs which enhance the effects of serotonergic
neurotransmission, such as tryptophan, fenfluramine, fentanyl, 5-HT agonists, or the herbal medicine
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
St. John’s Wort (hypericum perforatum) should be undertaken with caution and avoided whenever
possible due to the potential for pharmacodynamic interaction.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake
Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A
gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including Zoloft, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other
anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and
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For current labeling information, please visit https://www.fda.gov/drugsatfda
cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Zoloft and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See Information for
Patients.)
Hyponatremia–
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including ZOLOFT. In
many cases, this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L
have been reported. Elderly patients may be at greater risk of developing hyponatremia with
SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be
at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT should be considered in
patients with symptomatic hyponatremia and appropriate medical intervention should be
instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with Zoloft and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions:
is available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
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ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use
of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of Zoloft and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral
Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At
20
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For current labeling information, please visit https://www.fda.gov/drugsatfda
times, a slight haze may appear after mixing; this is normal. Note that caution should be
exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
Laboratory Tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in
patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive
test results may be expected for several days following discontinuation of sertraline therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline
from benzodiazepines.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-
administration to steady state was associated with a mean increase in pimozide AUC and Cmax
of about 40%, but was not associated with any changes in EKG. Since the highest recommended
pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT
interval and PK parameters at doses higher than 2 mg at this time are not known. While the
mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and
due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT
and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of Zoloft on valproate levels has not been evaluated in clinical trials. In the absence
of such data, it is recommended that plasma valproate levels be monitored following initiation of
Zoloft therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors–See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co-
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including Zoloft,
and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including
Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome). The concomitant
use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS
– Drug Interactions).
Triptans: There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including Zoloft,
with a triptan is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
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need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID
or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when Zoloft is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
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dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft and other SSRIs or SNRIs, late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. These findings are based on post marketing reports. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general
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population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six-
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with ZOLOFT during the third trimester, the physician should
carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic in the context of antidepressant
therapy at the beginning of pregnancy, women who discontinued antidepressant medication
during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of Zoloft in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-
week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly
25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based
upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week
pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
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Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for
major depressive disorder (n=373), there was a difference in weight change between sertraline
and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17),
in both cases representing a slight weight loss for sertraline compared to a slight gain for
placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for
placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for
placebo. There was a bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in adolescents. For children, about
7% had a weight loss > 7% of body weight compared to none of the placebo patients; for
adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the
placebo patients. A subset of these patients who completed the randomized controlled trials
(sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,
extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight
weeks of treatment for subjects with first exposure to sertraline during the open-label extension
study, similar to mean weight loss observed among sertraline treated subjects during the first
eight weeks of the randomized controlled trials. The subjects continuing in the open label study
began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects
who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24
weeks open label, n=68) had weight gain that was similar to that expected using data from age-
adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric
patients below the age of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
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663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide
28
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the prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
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TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
30
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
31
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TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
32
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
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difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
34
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Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-
interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
thrombocytopenia, lupus-like syndrome, serum sickness, , hyperglycemia, galactorrhea,
36
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hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis,
pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-
Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports
of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be
reversible with discontinuation of ZOLOFT) occurring in one or more patients include: elevated
enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver
failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
37
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Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
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during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
39
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Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition,
at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
40
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Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment. The physician may consider tapering
ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
41
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F)[see USP Controlled Room
Temperature].
ZOLOFT® Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only
LAB-0218-19.0
Revised August 2011
42
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For current labeling information, please visit https://www.fda.gov/drugsatfda
43
Medication Guide
ZOLOFT (ZOH-loft)
(sertraline hydrochloride)
(Tablets and Oral Concentrate (solution))
Read the Medication Guide that comes with ZOLOFT before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there
is something you do not understand or want to learn more about.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is the most important information I should know about ZOLOFT?
ZOLOFT and other antidepressant medicines may cause serious side effects, including:
1. Suicidal thoughts or actions:
•
ZOLOFT and other antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, or young adults within the first few months of treatment or when the dose is
changed.
•
Depression or other serious mental illnesses are the most important causes of suicidal thoughts or
actions.
•
Watch for these changes and call your healthcare provider right away if you notice:
•
New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
•
Pay particular attention to such changes when ZOLOFT is started or when the dose is changed.
Keep all follow-up visits with your healthcare provider and call between visits if you are worried
about symptoms.
Call your healthcare provider right away if you have any of the following symptoms, or call 911
if an emergency, especially if they are new, worse, or worry you:
•
attempts to commit suicide
•
acting on dangerous impulses
•
acting aggressive or violent
•
thoughts about suicide or dying
•
new or worse depression
•
new or worse anxiety or panic attacks
•
feeling agitated, restless, angry or irritable
•
trouble sleeping
•
an increase in activity or talking more than what is normal for you
•
other unusual changes in behavior or mood
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if
an emergency. ZOLOFT may be associated with these serious side effects:
2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be
life-threatening and may include:
•
agitation, hallucinations, coma or other changes in mental status
•
coordination problems or muscle twitching (overactive reflexes)
•
racing heartbeat, high or low blood pressure
•
sweating or fever
•
nausea, vomiting, or diarrhea
•
muscle rigidity
3. Severe allergic reactions:
•
trouble breathing
•
swelling of the face, tongue, eyes or mouth
•
rash, itchy welts (hives) or blisters, alone or with fever or joint pain
4. Abnormal bleeding: ZOLOFT and other antidepressant medicines may increase your risk of bleeding
or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal
anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.
5. Seizures or convulsions
6. Manic episodes:
•
greatly increased energy
44
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For current labeling information, please visit https://www.fda.gov/drugsatfda
•
severe trouble sleeping
•
racing thoughts
•
reckless behavior
•
unusually grand ideas
•
excessive happiness or irritability
•
talking more or faster than usual
7. Changes in appetite or weight. Children and adolescents should have height and weight monitored
during treatment.
8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may
include:
•
headache
•
weakness or feeling unsteady
•
confusion, problems concentrating or thinking or memory problems
Do not stop ZOLOFT without first talking to your healthcare provider. Stopping ZOLOFT too
quickly may cause serious symptoms including:
•
anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
•
headache, sweating, nausea, dizziness
•
electric shock-like sensations, shaking, confusion
What is ZOLOFT?
ZOLOFT is a prescription medicine used to treat depression. It is important to talk with your healthcare
provider about the risks of treating depression and also the risks of not treating it. You should discuss all
treatment choices with your healthcare provider. ZOLOFT is also used to treat:
•
Major Depressive Disorder (MDD)
•
Obsessive Compulsive Disorder (OCD)
•
Panic Disorder
•
Posttraumatic Stress Disorder (PTSD)
•
Social Anxiety Disorder
•
Premenstrual Dysphoric Disorder (PMDD)
Talk to your healthcare provider if you do not think that your condition is getting better with ZOLOFT
treatment.
Who should not take ZOLOFT?
Do not take ZOLOFT if you:
•
are allergic to sertraline or any of the ingredients in ZOLOFT. See the end of this Medication Guide
for a complete list of ingredients in ZOLOFT.
•
take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart
problems.
•
take Antabuse® (disulfiram) (if you are taking the liquid form of ZOLOFT) due to the alcohol
content.
•
take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are
not sure if you take an MAOI, including the antibiotic linezolid.
•
Do not take an MAOI within 2 weeks of stopping ZOLOFT.
•
Do not start ZOLOFT if you stopped taking an MAOI in the last 2 weeks.
People who take ZOLOFT close in time to an MAOI may have serious or even life-threatening
side effects. Get medical help right away if you have any of these symptoms:
•
high fever
•
uncontrolled muscle spasms
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
stiff muscles
•
rapid changes in heart rate or blood pressure
•
confusion
•
loss of consciousness (pass out)
What should I tell my healthcare provider before taking ZOLOFT? Ask if you are not sure.
Before starting ZOLOFT, tell your healthcare provider if you:
•
Are taking certain drugs such as:
•
Medicines used to treat migraine headaches such as:
o triptans
•
Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:
o tricyclic antidepressants
o lithium
o diazepam
o SSRIs
o SNRIs
o antipsychotic drugs
o valproate
•
Medicines used to treat seizures such as:
o phenytoin
•
Medicines used to treat pain such as:
o tramadol
•
Medicines used to thin your blood such as:
o warfarin
•
Medicines used to control your heartbeat such as :
o propafenone
o flecainide
o digitoxin
•
Medicines used to treat type II diabetes such as:
o tolbutamide
•
Cimetidine used to treat heartburn
•
Over-the-counter medicines or supplements such as:
o Aspirin or other NSAIDs
o tryptophan
o St. John’s Wort
•
have liver problems
•
have kidney problems.
•
have heart problems
•
have or had seizures or convulsions
•
have bipolar disorder or mania
•
have low sodium levels in your blood
•
have a history of a stroke
•
have high blood pressure
•
have or had bleeding problems
•
are pregnant or plan to become pregnant. It is not known if ZOLOFT will harm your unborn baby.
Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
•
are breast-feeding or plan to breast-feed. Some ZOLOFT may pass into your breast milk. Talk to your
healthcare provider about the best way to feed your baby while taking ZOLOFT.
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all the medicines that you take, including prescription and non-
prescription medicines, vitamins, and herbal supplements. ZOLOFT and some medicines may interact
with each other, may not work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell you if it is safe to take ZOLOFT with your other
medicines. Do not start or stop any medicine while taking ZOLOFT without talking to your healthcare
provider first.
If you take ZOLOFT, you should not take any other medicines that contain sertraline (sertraline HCl,
sertraline hydrochloride, etc.).
How should I take ZOLOFT?
•
Take ZOLOFT exactly as prescribed. Your healthcare provider may need to change the dose of
ZOLOFT until it is the right dose for you.
•
ZOLOFT Tablets may be taken with or without food.
•
ZOLOFT Oral Concentrate must be diluted before use:
o Follow the instructions carefully
o When diluting ZOLOFT Oral Concentrate, use ONLY water, ginger ale, lemon/lime soda,
lemonade, or orange juice.
o If you are sensitive to latex, be careful when using the dropper to dispense the Oral
Concentrate.
•
If you miss a dose of ZOLOFT, take the missed dose as soon as you remember. If it is almost time for
the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses
of ZOLOFT at the same time.
•
If you take too much ZOLOFT, call your healthcare provider or poison control center right away, or
get emergency treatment.
What should I avoid while taking ZOLOFT?
ZOLOFT can cause sleepiness or may affect your ability to make decisions, think clearly, or react
quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know
how ZOLOFT affects you. Do not drink alcohol while using ZOLOFT.
What are the possible side effects of ZOLOFT?
ZOLOFT may cause serious side effects, including:
• See “What is the most important information I should know about ZOLOFT?”
•
Feeling anxious or trouble sleeping
Common possible side effects in people who take ZOLOFT include:
• nausea, loss of appetite, diarrhea or indigestion
• change in sleep habits including increased sleepiness or insomnia
• increased sweating
• sexual problems including decreased libido and ejaculation failure
• tremor or shaking
• feeling tired or fatigued
• agitation
Other side effects in children and adolescents include:
• abnormal increase in muscle movement or agitation
• nose bleed
• urinating more often
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
• urinary incontinence
• aggressive reaction
• heavy menstrual periods
• possible slowed growth rate and weight change. Your child’s height and weight should be
monitored during treatment with ZOLOFT.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These
are not all the possible side effects of ZOLOFT. For more information, ask your healthcare provider or
pharmacist.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY
REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.
How should I store ZOLOFT?
•
Store ZOLOFT at room temperature, between 59°F and 86°F (15°C to 30°C).
•
Keep ZOLOFT bottle closed tightly.
Keep ZOLOFT and all medicines out of the reach of children.
General information about ZOLOFT
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use ZOLOFT for a condition for which it was not prescribed. Do not give ZOLOFT to other people, even
if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about ZOLOFT. If you would like
more information, talk with your healthcare provider. You may ask your healthcare provider or
pharmacist for information about ZOLOFT that is written for healthcare professionals.
For more information about ZOLOFT call 1-800-438-1985 or go to www.pfizer.com
What are the ingredients in ZOLOFT?
Active ingredient: sertraline hydrochloride
Inactive ingredients
•
Tablets: dibasic calcium phosphate dihydrate, D&C Yellow #10 aluminum lake (in 25 mg tablet),
FD&C Blue #1 aluminum lake (in 25 mg tablet), FD&C Red #40 aluminum lake (in 25 mg tablet),
FD&C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,
synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide
•
Oral concentration: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT)
Revised August 2011
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:04.372261
|
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|
11,761
|
ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
ZOLOFT or any other antidepressant in a child, adolescent, or young adult must balance this
risk with the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24; there was a
reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in
the risk of suicide. Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening, suicidality, or unusual
changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. ZOLOFT is not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD). (See
Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and
Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2HCl is represented by the following structural
formula:
1
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
tructu ral
for
mula
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,
synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
2
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
3
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age
(11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline
AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr.
Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower
AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data
suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric patients given their lower body
weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
4
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
5
Reference ID: 3536868
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reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total
score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for
age and gender effects on outcome did not suggest any differential responsiveness on the basis of
age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of 25% compared to baseline and a CGI-I
of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
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Reference ID: 3536868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
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As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this apparent
gender interaction is unknown at this time. There was insufficient information to determine the
effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I 3; (2) CAPS-2 score increased by 30% and by 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria
for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal
phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients; ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
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In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
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continuation treatment experienced a statistically significantly lower relapse rate over this 24
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following
8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled
trial. The usefulness of the drug in patients receiving ZOLOFT for extended periods should be
reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
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for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical
Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
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outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
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The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
The use of MAOIs intended to treat psychiatric disorders with ZOLOFT or within 14 days of
stopping treatment with ZOLOFT is contraindicated because of an increased risk of serotonin
syndrome. The use of ZOLOFT within 14 days of stopping an MAOI intended to treat
psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Starting ZOLOFT in a patient who is being treated with MAOIs such as linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
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Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults
with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of
2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in
risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost
all drugs studied. There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however,
were relatively stable within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
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It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management, in
order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
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depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has
been reported with SNRIs and SSRIs, including ZOLOFT, alone but particularly with
concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that
impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity,
myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin
syndrome.
The concomitant use of ZOLOFT with MAOIs intended to treat psychiatric disorders is
contraindicated. ZOLOFT should also not be started in a patient who is being treated with
MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that
provided information on the route of administration involved intravenous administration in the
dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by
other routes (such as oral tablets or local tissue injection) or at lower doses. There may be
circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or
intravenous methylene blue in a patient taking ZOLOFT. ZOLOFT should be discontinued
before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND
ADMINISTRATION).
If concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is
clinically warranted, patients should be made aware of a potential increased risk for serotonin
syndrome, particularly during treatment initiation and dose increases.
Treatment with ZOLOFT and any concomitant serotonergic agents should be discontinued
immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many
antidepressant drugs including Zoloft may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
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loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were
excluded from clinical studies during the product’s premarket testing. No seizures were observed
among approximately 3000 patients treated with ZOLOFT in the development program for major
depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age)
exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with ZOLOFT
During marketing of ZOLOFT and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with ZOLOFT.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including ZOLOFT, may increase the risk of bleeding events ranging from
ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening
hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants or other drugs known to affect platelet function may add to this risk. Case
reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
ZOLOFT and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean decrease
in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect
is unknown.
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Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP)
have been reported. The majority of reports occurred in patients with other risk factors for QTc
prolongation/TdP. Therefore Zoloft should be used with caution in patients with risk factors for
QTc prolongation.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance (See Information for
Patients).
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Hyponatremia–Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including ZOLOFT. In many cases, this hyponatremia appears to be the result of the syndrome
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT
should be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function– There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with ZOLOFT and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is
available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents of
the Medication Guide and to obtain answers to any questions they may have. The complete text
of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Families and
caregivers of patients should be advised to look for the emergence of such symptoms on a day-
to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s
prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an increased
risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
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Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
SNRIs and SSRIs, including ZOLOFT, and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Zoloft can cause mild pupillary dilation, which in
susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing
glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when
diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk
factor for angle closure glaucoma. Patients may wish to be examined to determine whether they
are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they
are susceptible.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to ZOLOFT
they should be careful doing activities when they need to be alert, such as driving a car or
operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs
that interfere with serotonin reuptake and these agents has been associated with an increased risk
of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant
use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any
OTC product should be initiated cautiously according to the directions of use given for the OTC
product.
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
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dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for persons with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
Laboratory Tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in
patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive
test results may be expected for several days following discontinuation of sertraline therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline
from benzodiazepines.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
Drugs that Prolong the QT Interval – The risk of QTc prolongation and/or ventricular
arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc
interval (e.g., some antipsychotics and antibiotics) (see PRECAUTIONS).
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
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In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.)
co-administration to steady state was associated with a mean increase in pimozide AUC and
Cmax of about 40%, but was not associated with any changes in EKG. Since the highest
recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the
effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.
While the mechanism of this interaction is unknown, due to the narrow therapeutic index of
pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration
of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of ZOLOFT therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of ZOLOFT on valproate levels has not been evaluated in clinical trials. In the
absence of such data, it is recommended that plasma valproate levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors – See CONTRAINDICATIONS, WARNINGS, and DOSAGE
AND ADMINISTRATION.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
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significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs – See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND
ADMINISTRATION.
Triptans – There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including
ZOLOFT, with a triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases (see WARNINGS – Serotonin
Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
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Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) –
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when ZOLOFT is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
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Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects - Neonates exposed to ZOLOFT and other SSRIs or
serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Reported clinical findings
have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,
irritability, and constant crying. These features are consistent with either a direct toxic effect of
SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some
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cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin
Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general
population and is associated with substantial neonatal morbidity and mortality. Several recent
epidemiologic studies suggest a positive statistical association between SSRI use (including
ZOLOFT) in pregnancy and PPHN. Other studies do not show a significant statistical
association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant
women with a history of major depression, who were either on antidepressants or had received
antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.
Women who discontinued antidepressant medication during pregnancy showed a significant
increase in relapse of their major depression compared to those women who remained on
antidepressant medication throughout pregnancy.
When treating a pregnant woman with ZOLOFT, the physician should carefully consider both
the potential risks of taking an SSRI, along with the established benefits of treating depression
with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with ZOLOFT, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of ZOLOFT in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial
12-week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either
25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in
weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day
based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12
week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
26
Reference ID: 3536868
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Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two
10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major
depressive disorder (n=373), there was a difference in weight change between sertraline and
placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in
both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.
At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At
baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo.
There was a bigger difference between sertraline and placebo in the proportion of outliers for
clinically important weight loss in children than in adolescents. For children, about 7% had a
weight loss > 7% of body weight compared to none of the placebo patients; for adolescents,
about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients.
A subset of these patients who completed the randomized controlled trials (sertraline n=99,
placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A
mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for
subjects with first exposure to sertraline during the open-label extension study, similar to mean
weight loss observed among sertraline treated subjects during the first eight weeks of the
randomized controlled trials. The subjects continuing in the open label study began gaining
weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed
34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label,
n=68) had weight gain that was similar to that expected using data from age-adjusted peers.
Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with
an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age
of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
27
Reference ID: 3536868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects 65 years of age, of those, 180 were 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
28
Reference ID: 3536868
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involving different treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
29
Reference ID: 3536868
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TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
30
Reference ID: 3536868
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
31
Reference ID: 3536868
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TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had an
incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
32
Reference ID: 3536868
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
33
Reference ID: 3536868
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them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
34
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more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, angle-closure glaucoma, priapism,
vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
35
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias,
QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias),
cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming
syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
36
Reference ID: 3536868
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thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia,
galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin
syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be
fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous
disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority
of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in one or more
patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice,
abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in
fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage
to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia,
somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The
most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage
were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor, syncope and Torsade de Pointes.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
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Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
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ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response to
the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
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during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the onset
of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to
Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an
MAOI intended to treat psychiatric disorders and initiation of therapy with ZOLOFT.
Conversely, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI
intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of ZOLOFT With Other MAOIs Such as Linezolid or Methylene Blue: Do not start
ZOLOFT in a patient who is being treated with linezolid or intravenous methylene blue because
there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of
a psychiatric condition, other interventions, including hospitalization, should be considered (see
CONTRAINDICATIONS).
In some cases, a patient already receiving ZOLOFT therapy may require urgent treatment with
linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous
methylene blue treatment are not available and the potential benefits of linezolid or intravenous
methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular
patient, ZOLOFT should be stopped promptly, and linezolid or intravenous methylene blue can
be administered. The patient should be monitored for symptoms of serotonin syndrome for 2
weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with ZOLOFT may be resumed 24 hours after the last dose of linezolid or
intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by
local injection) or in intravenous doses much lower than 1 mg/kg with ZOLOFT is unclear. The
clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin
syndrome with such use (see WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
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impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment.
Discontinuation of Treatment with ZOLOFT
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
NDC 0049-4900-66
Bottles of 100
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NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25C (77F); excursions permitted to 15 - 30C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only company logo
LAB-0218-32.0
Revised May 2014
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Medication Guide
ZOLOFT (ZOH-loft)
(sertraline hydrochloride)
(Tablets and Oral Concentrate (solution))
Read the Medication Guide that comes with ZOLOFT before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there
is something you do not understand or want to learn more about.
What is the most important information I
should know about ZOLOFT?
ZOLOFT and other antidepressant medicines
may cause serious side effects, including:
1. Suicidal thoughts or actions:
ZOLOFT and other antidepressant
medicines may increase suicidal thoughts
or actions in some children, teenagers, or
young adults within the first few months of
treatment or when the dose is changed.
Depression or other serious mental illnesses
are the most important causes of suicidal
thoughts or actions.
Watch for these changes and call your
healthcare provider right away if you notice:
New or sudden changes in mood,
behavior, actions, thoughts, or feelings,
especially if severe.
Pay particular attention to such changes
when ZOLOFT is started or when the
dose is changed.
Keep all follow-up visits with your
healthcare provider and call between visits if
you are worried about symptoms.
Call your healthcare provider right away
if you have any of the following
symptoms, or call 911 if an emergency,
especially if they are new, worse, or worry
you:
attempts to commit suicide
acting on dangerous impulses
acting aggressive or violent
thoughts about suicide or dying
new or worse depression
new or worse anxiety or panic
attacks
feeling agitated, restless, angry or
irritable
trouble sleeping
an increase in activity or talking
more than what is normal for you
other unusual changes in behavior
or mood
Call your healthcare provider right away if
you have any of the following symptoms, or
call 911 if an emergency. ZOLOFT may be
associated with these serious side effects:
2. Serotonin Syndrome
This condition can be life-threatening and
may include:
agitation, hallucinations, coma or other
changes in mental status
coordination problems or muscle
twitching (overactive reflexes)
racing heartbeat, high or low blood
pressure
sweating or fever
nausea, vomiting, or diarrhea
muscle rigidity
3. Severe allergic reactions:
trouble breathing
swelling of the face, tongue, eyes or
mouth
rash, itchy welts (hives) or blisters,
alone or with fever or joint pain
4. Abnormal bleeding: ZOLOFT and other
antidepressant medicines may increase your
risk of bleeding or bruising, especially if you
take the blood thinner warfarin (Coumadin® ,
Jantoven®), a non-steroidal anti-
inflammatory drug (NSAIDs, like ibuprofen
or naproxen), or aspirin.
5. Seizures or convulsions
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6. Manic episodes:
Premenstrual Dysphoric Disorder (PMDD)
greatly increased energy
Talk to your healthcare provider if you do not
severe trouble sleeping
think that your condition is getting better with
racing thoughts
ZOLOFT treatment.
reckless behavior
Who should not take ZOLOFT?
unusually grand ideas
excessive happiness or irritability
talking more or faster than usual
7. Changes in appetite or weight. Children
and adolescents should have height and
weight monitored during treatment.
8. Low salt (sodium) levels in the blood.
Elderly people may be at greater risk for
this. Symptoms may include:
headache
weakness or feeling unsteady
confusion, problems concentrating or
thinking or memory problems
9. Visual problems
eye pain
changes in vision
swelling or redness in or around the eye
Only some people are at risk for these
problems. You may want to undergo an eye
examination to see if you are at risk and
receive preventative treatment if you are.
Do not stop ZOLOFT without first talking to
your healthcare provider. Stopping ZOLOFT
too quickly may cause serious symptoms
including:
anxiety, irritability, high or low mood,
feeling restless or changes in sleep habits
headache, sweating, nausea, dizziness
electric shock-like sensations, shaking,
confusion
What is ZOLOFT?
ZOLOFT is a prescription medicine used to treat
depression. It is important to talk with your
healthcare provider about the risks of treating
depression and also the risks of not treating it.
You should discuss all treatment choices with
your healthcare provider. ZOLOFT is also used
to treat:
Major Depressive Disorder (MDD)
Obsessive Compulsive Disorder (OCD)
Panic Disorder
Posttraumatic Stress Disorder (PTSD)
Social Anxiety Disorder
Do not take ZOLOFT if you:
are allergic to sertraline or any of the
ingredients in ZOLOFT. See the end of this
Medication Guide for a complete list of
ingredients in ZOLOFT.
take the antipsychotic medicine pimozide
(Orap®) because this can cause serious
heart problems.
take Antabuse® (disulfiram) (if you are
taking the liquid form of ZOLOFT) due to
the alcohol content.
take a monoamine oxidase inhibitor
(MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an
MAOI, including the antibiotic linezolid.
Do not take an MAOI within 2 weeks of
stopping ZOLOFT unless directed to do so
by your physician.
Do not start ZOLOFT if you stopped taking
an MAOI in the last 2 weeks unless directed
to do so by your physician.
People who take ZOLOFT close in time to
an MAOI may have serious or even life-
threatening side effects. Get medical help
right away if you have any of these
symptoms:
high fever
uncontrolled muscle spasms
stiff muscles
rapid changes in heart rate or blood
pressure
confusion
loss of consciousness (pass out)
What should I tell my healthcare provider
before taking ZOLOFT? Ask if you are not
sure.
Before starting ZOLOFT, tell your healthcare
provider if you:
Are taking certain drugs such as:
Medicines used to treat migraine
headaches such as:
o triptans
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Medicines used to treat mood, anxiety,
psychotic or thought disorders, such as:
o tricyclic antidepressants
o lithium
o diazepam
o SSRIs
o SNRIs
o antipsychotic drugs
o valproate
Medicines used to treat seizures such as:
o phenytoin
Medicines used to treat pain such as:
o tramadol
Medicines used to thin your blood such
as:
o warfarin
Medicines used to control your heartbeat
such as :
o propafenone
o flecainide
o digitoxin
Medicines used to treat type II diabetes
such as:
o tolbutamide
Cimetidine used to treat heartburn
Over-the-counter medicines or
supplements such as:
o Aspirin or other NSAIDs
o tryptophan
o St. John’s Wort
have liver problems
have kidney problems.
have heart problems
have or had seizures or convulsions
have bipolar disorder or mania
have low sodium levels in your blood
have a history of a stroke
have high blood pressure
have or had bleeding problems
are pregnant or plan to become pregnant. It
is not known if ZOLOFT will harm your
unborn baby. Talk to your healthcare
provider about the benefits and risks of
treating depression during pregnancy.
are breast-feeding or plan to breast-feed.
Some ZOLOFT may pass into your breast
milk. Talk to your healthcare provider about
the best way to feed your baby while taking
ZOLOFT.
Tell your healthcare provider about all the
medicines that you take, including prescription
and non-prescription medicines, vitamins, and
herbal supplements. ZOLOFT and some
medicines may interact with each other, may not
work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell
you if it is safe to take ZOLOFT with your other
medicines. Do not start or stop any medicine
while taking ZOLOFT without talking to your
healthcare provider first.
If you take ZOLOFT, you should not take any
other medicines that contain sertraline (sertraline
HCl, sertraline hydrochloride, etc.).
How should I take ZOLOFT?
Take ZOLOFT exactly as prescribed. Your
healthcare provider may need to change the
dose of ZOLOFT until it is the right dose for
you.
ZOLOFT Tablets may be taken with or
without food.
ZOLOFT Oral Concentrate must be diluted
before use:
o Follow the instructions carefully
o When diluting ZOLOFT Oral
Concentrate, use ONLY water,
ginger ale, lemon/lime soda,
lemonade, or orange juice.
o If you are sensitive to latex, be
careful when using the dropper to
dispense the Oral Concentrate.
If you miss a dose of ZOLOFT, take the
missed dose as soon as you remember. If it
is almost time for the next dose, skip the
missed dose and take your next dose at the
regular time. Do not take two doses of
ZOLOFT at the same time.
If you take too much ZOLOFT, call your
healthcare provider or poison control center
right away, or get emergency treatment.
What should I avoid while taking ZOLOFT?
ZOLOFT can cause sleepiness or may affect
your ability to make decisions, think clearly, or
react quickly. You should not drive, operate
heavy machinery, or do other dangerous
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activities until you know how ZOLOFT affects
you. Do not drink alcohol while using ZOLOFT.
What are the possible side effects of
ZOLOFT?
ZOLOFT may cause serious side effects,
including:
See “What is the most important
information I should know about
ZOLOFT?”
Feeling anxious or trouble sleeping
Common possible side effects in people who
take ZOLOFT include:
nausea, loss of appetite, diarrhea or
indigestion
change in sleep habits including
increased sleepiness or insomnia
increased sweating
sexual problems including decreased
libido and ejaculation failure
tremor or shaking
feeling tired or fatigued
agitation
Other side effects in children and adolescents
include:
abnormal increase in muscle movement
or agitation
nose bleed
urinating more often
urinary incontinence
aggressive reaction
heavy menstrual periods
possible slowed growth rate and weight
change. Your child’s height and weight
should be monitored during treatment
with ZOLOFT.
Tell your healthcare provider if you have any
side effect that bothers you or that does not go
away. These are not all the possible side effects
of ZOLOFT. For more information, ask your
healthcare provider or pharmacist.
CALL YOUR DOCTOR FOR MEDICAL
ADVICE ABOUT SIDE EFFECTS. YOU
MAY REPORT SIDE EFFECTS TO THE
FDA AT 1-800-FDA-1088.
How should I store ZOLOFT?
Store ZOLOFT at room temperature,
between 59°F and 86°F (15°C to 30°C).
Keep ZOLOFT bottle closed tightly.
Keep ZOLOFT and all medicines out of the
reach of children.
General information about ZOLOFT
Medicines are sometimes prescribed for
purposes other than those listed in a Medication
Guide. Do not use ZOLOFT for a condition for
which it was not prescribed. Do not give
ZOLOFT to other people, even if they have the
same condition. It may harm them.
This Medication Guide summarizes the most
important information about ZOLOFT. If you
would like more information, talk with your
healthcare provider. You may ask your
healthcare provider or pharmacist for
information about ZOLOFT that is written for
healthcare professionals.
For more information about ZOLOFT call
1-800-438-1985 or go to www.pfizer.com
What are the ingredients in ZOLOFT?
Active ingredient: sertraline hydrochloride
Inactive ingredients
Tablets: dibasic calcium phosphate
dihydrate, D&C Yellow #10 aluminum lake
(in 25 mg tablet), FD&C Blue #1 aluminum
lake (in 25 mg tablet), FD&C Red #40
aluminum lake (in 25 mg tablet), FD&C
Blue #2 aluminum lake (in 50 mg tablet),
hydroxypropyl cellulose, hypromellose,
magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, synthetic
yellow iron oxide (in 100 mg tablet), and
titanium dioxide
Oral concentration: glycerin, alcohol
(12%), menthol, butylated hydroxytoluene
(BHT)
This Medication Guide has been approved by
the U.S. Food and Drug Administration
46
Reference ID: 3536868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
LAB-0540-4.0
Revised May 2014
Reference ID: 3536868
47
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|
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11,762
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ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
ZOLOFT or any other antidepressant in a child, adolescent, or young adult must balance this
risk with the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24; there was a
reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in
the risk of suicide. Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening, suicidality, or unusual
changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. ZOLOFT is not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD). (See
Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and
Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2HCl is represented by the following structural
formula:
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s
tructu ral
for
mula
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,
synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
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Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
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Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age
(11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline
AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr.
Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower
AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data
suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric patients given their lower body
weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
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Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
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reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total
score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for
age and gender effects on outcome did not suggest any differential responsiveness on the basis of
age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of 25% compared to baseline and a CGI-I
of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
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Reference ID: 3536868
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difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
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As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this apparent
gender interaction is unknown at this time. There was insufficient information to determine the
effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I 3; (2) CAPS-2 score increased by 30% and by 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria
for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal
phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients; ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
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In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
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continuation treatment experienced a statistically significantly lower relapse rate over this 24
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following
8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled
trial. The usefulness of the drug in patients receiving ZOLOFT for extended periods should be
reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
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for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical
Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
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outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
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The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
The use of MAOIs intended to treat psychiatric disorders with ZOLOFT or within 14 days of
stopping treatment with ZOLOFT is contraindicated because of an increased risk of serotonin
syndrome. The use of ZOLOFT within 14 days of stopping an MAOI intended to treat
psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Starting ZOLOFT in a patient who is being treated with MAOIs such as linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
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Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults
with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of
2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in
risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost
all drugs studied. There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however,
were relatively stable within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
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It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management, in
order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
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depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has
been reported with SNRIs and SSRIs, including ZOLOFT, alone but particularly with
concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that
impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity,
myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin
syndrome.
The concomitant use of ZOLOFT with MAOIs intended to treat psychiatric disorders is
contraindicated. ZOLOFT should also not be started in a patient who is being treated with
MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that
provided information on the route of administration involved intravenous administration in the
dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by
other routes (such as oral tablets or local tissue injection) or at lower doses. There may be
circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or
intravenous methylene blue in a patient taking ZOLOFT. ZOLOFT should be discontinued
before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND
ADMINISTRATION).
If concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is
clinically warranted, patients should be made aware of a potential increased risk for serotonin
syndrome, particularly during treatment initiation and dose increases.
Treatment with ZOLOFT and any concomitant serotonergic agents should be discontinued
immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many
antidepressant drugs including Zoloft may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
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loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were
excluded from clinical studies during the product’s premarket testing. No seizures were observed
among approximately 3000 patients treated with ZOLOFT in the development program for major
depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age)
exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with ZOLOFT
During marketing of ZOLOFT and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with ZOLOFT.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including ZOLOFT, may increase the risk of bleeding events ranging from
ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening
hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants or other drugs known to affect platelet function may add to this risk. Case
reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
ZOLOFT and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean decrease
in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect
is unknown.
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Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP)
have been reported. The majority of reports occurred in patients with other risk factors for QTc
prolongation/TdP. Therefore Zoloft should be used with caution in patients with risk factors for
QTc prolongation.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance (See Information for
Patients).
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Hyponatremia–Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including ZOLOFT. In many cases, this hyponatremia appears to be the result of the syndrome
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT
should be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function– There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with ZOLOFT and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is
available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents of
the Medication Guide and to obtain answers to any questions they may have. The complete text
of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Families and
caregivers of patients should be advised to look for the emergence of such symptoms on a day-
to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s
prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an increased
risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
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Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
SNRIs and SSRIs, including ZOLOFT, and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Zoloft can cause mild pupillary dilation, which in
susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing
glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when
diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk
factor for angle closure glaucoma. Patients may wish to be examined to determine whether they
are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they
are susceptible.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to ZOLOFT
they should be careful doing activities when they need to be alert, such as driving a car or
operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs
that interfere with serotonin reuptake and these agents has been associated with an increased risk
of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant
use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any
OTC product should be initiated cautiously according to the directions of use given for the OTC
product.
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
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dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for persons with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
Laboratory Tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in
patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive
test results may be expected for several days following discontinuation of sertraline therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline
from benzodiazepines.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
Drugs that Prolong the QT Interval – The risk of QTc prolongation and/or ventricular
arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc
interval (e.g., some antipsychotics and antibiotics) (see PRECAUTIONS).
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
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In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.)
co-administration to steady state was associated with a mean increase in pimozide AUC and
Cmax of about 40%, but was not associated with any changes in EKG. Since the highest
recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the
effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.
While the mechanism of this interaction is unknown, due to the narrow therapeutic index of
pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration
of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of ZOLOFT therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of ZOLOFT on valproate levels has not been evaluated in clinical trials. In the
absence of such data, it is recommended that plasma valproate levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors – See CONTRAINDICATIONS, WARNINGS, and DOSAGE
AND ADMINISTRATION.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
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significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs – See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND
ADMINISTRATION.
Triptans – There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including
ZOLOFT, with a triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases (see WARNINGS – Serotonin
Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
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Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) –
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when ZOLOFT is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
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Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects - Neonates exposed to ZOLOFT and other SSRIs or
serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Reported clinical findings
have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,
irritability, and constant crying. These features are consistent with either a direct toxic effect of
SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some
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cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin
Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general
population and is associated with substantial neonatal morbidity and mortality. Several recent
epidemiologic studies suggest a positive statistical association between SSRI use (including
ZOLOFT) in pregnancy and PPHN. Other studies do not show a significant statistical
association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant
women with a history of major depression, who were either on antidepressants or had received
antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.
Women who discontinued antidepressant medication during pregnancy showed a significant
increase in relapse of their major depression compared to those women who remained on
antidepressant medication throughout pregnancy.
When treating a pregnant woman with ZOLOFT, the physician should carefully consider both
the potential risks of taking an SSRI, along with the established benefits of treating depression
with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with ZOLOFT, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of ZOLOFT in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial
12-week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either
25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in
weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day
based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12
week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
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Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two
10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major
depressive disorder (n=373), there was a difference in weight change between sertraline and
placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in
both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.
At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At
baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo.
There was a bigger difference between sertraline and placebo in the proportion of outliers for
clinically important weight loss in children than in adolescents. For children, about 7% had a
weight loss > 7% of body weight compared to none of the placebo patients; for adolescents,
about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients.
A subset of these patients who completed the randomized controlled trials (sertraline n=99,
placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A
mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for
subjects with first exposure to sertraline during the open-label extension study, similar to mean
weight loss observed among sertraline treated subjects during the first eight weeks of the
randomized controlled trials. The subjects continuing in the open label study began gaining
weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed
34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label,
n=68) had weight gain that was similar to that expected using data from age-adjusted peers.
Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with
an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age
of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
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Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects 65 years of age, of those, 180 were 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
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involving different treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
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TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive
Disorder/Other*
OCD
Panic Disorder
PTSD
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Social Anxiety Disorder
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
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(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
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Reference ID: 3536868
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TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
Ejaculation Failure(1)
14
1
Mouth Dry
14
8
Sweating Increased
7
2
Center. & Periph. Nerv. System Disorders
Somnolence
13
7
Dizziness
12
7
Headache
25
23
Paresthesia
2
1
Tremor
8
2
Disorders of Skin and Appendages
Rash
3
2
Gastrointestinal Disorders
Anorexia
6
2
Constipation
6
4
Diarrhea/Loose Stools
20
10
Dyspepsia
8
4
Nausea
25
11
Vomiting
4
2
General
Fatigue
12
7
Psychiatric Disorders
Agitation
5
3
Anxiety
4
3
Insomnia
21
11
Libido Decreased
6
2
Nervousness
5
4
Special Senses
Vision Abnormal
3
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had an
incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
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Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)
Major
Depressive
Disorder/
Other*
(N=861)
OCD
(N=533)
Panic
Disorder
(N=430)
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation
–
1%
–
2%
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools
2%
2%
2%
1%
–
2%
–
–
Dizziness
–
–
1%
–
–
–
–
–
Dry Mouth
–
1%
–
–
–
–
–
–
Dyspepsia
–
–
–
1%
–
–
–
–
Ejaculation
Failure(1)
1%
1%
1%
2%
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache
1%
2%
–
–
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia
2%
1%
3%
2%
–
–
1%
3%
Nausea
3%
4%
3%
3%
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence
1%
1%
2%
2%
–
–
–
–
Tremor
–
2%
–
–
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
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them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
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more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, angle-closure glaucoma, priapism,
vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
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Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias,
QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias),
cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming
syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
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thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia,
galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin
syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be
fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous
disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority
of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in one or more
patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice,
abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in
fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage
to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia,
somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The
most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage
were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor, syncope and Torsade de Pointes.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
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Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
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ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response to
the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
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during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the onset
of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to
Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an
MAOI intended to treat psychiatric disorders and initiation of therapy with ZOLOFT.
Conversely, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI
intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of ZOLOFT With Other MAOIs Such as Linezolid or Methylene Blue: Do not start
ZOLOFT in a patient who is being treated with linezolid or intravenous methylene blue because
there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of
a psychiatric condition, other interventions, including hospitalization, should be considered (see
CONTRAINDICATIONS).
In some cases, a patient already receiving ZOLOFT therapy may require urgent treatment with
linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous
methylene blue treatment are not available and the potential benefits of linezolid or intravenous
methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular
patient, ZOLOFT should be stopped promptly, and linezolid or intravenous methylene blue can
be administered. The patient should be monitored for symptoms of serotonin syndrome for 2
weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with ZOLOFT may be resumed 24 hours after the last dose of linezolid or
intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by
local injection) or in intravenous doses much lower than 1 mg/kg with ZOLOFT is unclear. The
clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin
syndrome with such use (see WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. If sertraline is administered to patients with liver
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impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment.
Discontinuation of Treatment with ZOLOFT
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
NDC 0049-4900-66
Bottles of 100
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NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25C (77F); excursions permitted to 15 - 30C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only company logo
LAB-0218-32.0
Revised May 2014
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Medication Guide
ZOLOFT (ZOH-loft)
(sertraline hydrochloride)
(Tablets and Oral Concentrate (solution))
Read the Medication Guide that comes with ZOLOFT before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there
is something you do not understand or want to learn more about.
What is the most important information I
should know about ZOLOFT?
ZOLOFT and other antidepressant medicines
may cause serious side effects, including:
1. Suicidal thoughts or actions:
ZOLOFT and other antidepressant
medicines may increase suicidal thoughts
or actions in some children, teenagers, or
young adults within the first few months of
treatment or when the dose is changed.
Depression or other serious mental illnesses
are the most important causes of suicidal
thoughts or actions.
Watch for these changes and call your
healthcare provider right away if you notice:
New or sudden changes in mood,
behavior, actions, thoughts, or feelings,
especially if severe.
Pay particular attention to such changes
when ZOLOFT is started or when the
dose is changed.
Keep all follow-up visits with your
healthcare provider and call between visits if
you are worried about symptoms.
Call your healthcare provider right away
if you have any of the following
symptoms, or call 911 if an emergency,
especially if they are new, worse, or worry
you:
attempts to commit suicide
acting on dangerous impulses
acting aggressive or violent
thoughts about suicide or dying
new or worse depression
new or worse anxiety or panic
attacks
feeling agitated, restless, angry or
irritable
trouble sleeping
an increase in activity or talking
more than what is normal for you
other unusual changes in behavior
or mood
Call your healthcare provider right away if
you have any of the following symptoms, or
call 911 if an emergency. ZOLOFT may be
associated with these serious side effects:
2. Serotonin Syndrome
This condition can be life-threatening and
may include:
agitation, hallucinations, coma or other
changes in mental status
coordination problems or muscle
twitching (overactive reflexes)
racing heartbeat, high or low blood
pressure
sweating or fever
nausea, vomiting, or diarrhea
muscle rigidity
3. Severe allergic reactions:
trouble breathing
swelling of the face, tongue, eyes or
mouth
rash, itchy welts (hives) or blisters,
alone or with fever or joint pain
4. Abnormal bleeding: ZOLOFT and other
antidepressant medicines may increase your
risk of bleeding or bruising, especially if you
take the blood thinner warfarin (Coumadin® ,
Jantoven®), a non-steroidal anti-
inflammatory drug (NSAIDs, like ibuprofen
or naproxen), or aspirin.
5. Seizures or convulsions
43
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Manic episodes:
Premenstrual Dysphoric Disorder (PMDD)
greatly increased energy
Talk to your healthcare provider if you do not
severe trouble sleeping
think that your condition is getting better with
racing thoughts
ZOLOFT treatment.
reckless behavior
Who should not take ZOLOFT?
unusually grand ideas
excessive happiness or irritability
talking more or faster than usual
7. Changes in appetite or weight. Children
and adolescents should have height and
weight monitored during treatment.
8. Low salt (sodium) levels in the blood.
Elderly people may be at greater risk for
this. Symptoms may include:
headache
weakness or feeling unsteady
confusion, problems concentrating or
thinking or memory problems
9. Visual problems
eye pain
changes in vision
swelling or redness in or around the eye
Only some people are at risk for these
problems. You may want to undergo an eye
examination to see if you are at risk and
receive preventative treatment if you are.
Do not stop ZOLOFT without first talking to
your healthcare provider. Stopping ZOLOFT
too quickly may cause serious symptoms
including:
anxiety, irritability, high or low mood,
feeling restless or changes in sleep habits
headache, sweating, nausea, dizziness
electric shock-like sensations, shaking,
confusion
What is ZOLOFT?
ZOLOFT is a prescription medicine used to treat
depression. It is important to talk with your
healthcare provider about the risks of treating
depression and also the risks of not treating it.
You should discuss all treatment choices with
your healthcare provider. ZOLOFT is also used
to treat:
Major Depressive Disorder (MDD)
Obsessive Compulsive Disorder (OCD)
Panic Disorder
Posttraumatic Stress Disorder (PTSD)
Social Anxiety Disorder
Do not take ZOLOFT if you:
are allergic to sertraline or any of the
ingredients in ZOLOFT. See the end of this
Medication Guide for a complete list of
ingredients in ZOLOFT.
take the antipsychotic medicine pimozide
(Orap®) because this can cause serious
heart problems.
take Antabuse® (disulfiram) (if you are
taking the liquid form of ZOLOFT) due to
the alcohol content.
take a monoamine oxidase inhibitor
(MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an
MAOI, including the antibiotic linezolid.
Do not take an MAOI within 2 weeks of
stopping ZOLOFT unless directed to do so
by your physician.
Do not start ZOLOFT if you stopped taking
an MAOI in the last 2 weeks unless directed
to do so by your physician.
People who take ZOLOFT close in time to
an MAOI may have serious or even life-
threatening side effects. Get medical help
right away if you have any of these
symptoms:
high fever
uncontrolled muscle spasms
stiff muscles
rapid changes in heart rate or blood
pressure
confusion
loss of consciousness (pass out)
What should I tell my healthcare provider
before taking ZOLOFT? Ask if you are not
sure.
Before starting ZOLOFT, tell your healthcare
provider if you:
Are taking certain drugs such as:
Medicines used to treat migraine
headaches such as:
o triptans
44
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medicines used to treat mood, anxiety,
psychotic or thought disorders, such as:
o tricyclic antidepressants
o lithium
o diazepam
o SSRIs
o SNRIs
o antipsychotic drugs
o valproate
Medicines used to treat seizures such as:
o phenytoin
Medicines used to treat pain such as:
o tramadol
Medicines used to thin your blood such
as:
o warfarin
Medicines used to control your heartbeat
such as :
o propafenone
o flecainide
o digitoxin
Medicines used to treat type II diabetes
such as:
o tolbutamide
Cimetidine used to treat heartburn
Over-the-counter medicines or
supplements such as:
o Aspirin or other NSAIDs
o tryptophan
o St. John’s Wort
have liver problems
have kidney problems.
have heart problems
have or had seizures or convulsions
have bipolar disorder or mania
have low sodium levels in your blood
have a history of a stroke
have high blood pressure
have or had bleeding problems
are pregnant or plan to become pregnant. It
is not known if ZOLOFT will harm your
unborn baby. Talk to your healthcare
provider about the benefits and risks of
treating depression during pregnancy.
are breast-feeding or plan to breast-feed.
Some ZOLOFT may pass into your breast
milk. Talk to your healthcare provider about
the best way to feed your baby while taking
ZOLOFT.
Tell your healthcare provider about all the
medicines that you take, including prescription
and non-prescription medicines, vitamins, and
herbal supplements. ZOLOFT and some
medicines may interact with each other, may not
work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell
you if it is safe to take ZOLOFT with your other
medicines. Do not start or stop any medicine
while taking ZOLOFT without talking to your
healthcare provider first.
If you take ZOLOFT, you should not take any
other medicines that contain sertraline (sertraline
HCl, sertraline hydrochloride, etc.).
How should I take ZOLOFT?
Take ZOLOFT exactly as prescribed. Your
healthcare provider may need to change the
dose of ZOLOFT until it is the right dose for
you.
ZOLOFT Tablets may be taken with or
without food.
ZOLOFT Oral Concentrate must be diluted
before use:
o Follow the instructions carefully
o When diluting ZOLOFT Oral
Concentrate, use ONLY water,
ginger ale, lemon/lime soda,
lemonade, or orange juice.
o If you are sensitive to latex, be
careful when using the dropper to
dispense the Oral Concentrate.
If you miss a dose of ZOLOFT, take the
missed dose as soon as you remember. If it
is almost time for the next dose, skip the
missed dose and take your next dose at the
regular time. Do not take two doses of
ZOLOFT at the same time.
If you take too much ZOLOFT, call your
healthcare provider or poison control center
right away, or get emergency treatment.
What should I avoid while taking ZOLOFT?
ZOLOFT can cause sleepiness or may affect
your ability to make decisions, think clearly, or
react quickly. You should not drive, operate
heavy machinery, or do other dangerous
45
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
activities until you know how ZOLOFT affects
you. Do not drink alcohol while using ZOLOFT.
What are the possible side effects of
ZOLOFT?
ZOLOFT may cause serious side effects,
including:
See “What is the most important
information I should know about
ZOLOFT?”
Feeling anxious or trouble sleeping
Common possible side effects in people who
take ZOLOFT include:
nausea, loss of appetite, diarrhea or
indigestion
change in sleep habits including
increased sleepiness or insomnia
increased sweating
sexual problems including decreased
libido and ejaculation failure
tremor or shaking
feeling tired or fatigued
agitation
Other side effects in children and adolescents
include:
abnormal increase in muscle movement
or agitation
nose bleed
urinating more often
urinary incontinence
aggressive reaction
heavy menstrual periods
possible slowed growth rate and weight
change. Your child’s height and weight
should be monitored during treatment
with ZOLOFT.
Tell your healthcare provider if you have any
side effect that bothers you or that does not go
away. These are not all the possible side effects
of ZOLOFT. For more information, ask your
healthcare provider or pharmacist.
CALL YOUR DOCTOR FOR MEDICAL
ADVICE ABOUT SIDE EFFECTS. YOU
MAY REPORT SIDE EFFECTS TO THE
FDA AT 1-800-FDA-1088.
How should I store ZOLOFT?
Store ZOLOFT at room temperature,
between 59°F and 86°F (15°C to 30°C).
Keep ZOLOFT bottle closed tightly.
Keep ZOLOFT and all medicines out of the
reach of children.
General information about ZOLOFT
Medicines are sometimes prescribed for
purposes other than those listed in a Medication
Guide. Do not use ZOLOFT for a condition for
which it was not prescribed. Do not give
ZOLOFT to other people, even if they have the
same condition. It may harm them.
This Medication Guide summarizes the most
important information about ZOLOFT. If you
would like more information, talk with your
healthcare provider. You may ask your
healthcare provider or pharmacist for
information about ZOLOFT that is written for
healthcare professionals.
For more information about ZOLOFT call
1-800-438-1985 or go to www.pfizer.com
What are the ingredients in ZOLOFT?
Active ingredient: sertraline hydrochloride
Inactive ingredients
Tablets: dibasic calcium phosphate
dihydrate, D&C Yellow #10 aluminum lake
(in 25 mg tablet), FD&C Blue #1 aluminum
lake (in 25 mg tablet), FD&C Red #40
aluminum lake (in 25 mg tablet), FD&C
Blue #2 aluminum lake (in 50 mg tablet),
hydroxypropyl cellulose, hypromellose,
magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, synthetic
yellow iron oxide (in 100 mg tablet), and
titanium dioxide
Oral concentration: glycerin, alcohol
(12%), menthol, butylated hydroxytoluene
(BHT)
This Medication Guide has been approved by
the U.S. Food and Drug Administration
46
Reference ID: 3536868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
LAB-0540-4.0
Revised May 2014
Reference ID: 3536868
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:04.685449
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019839s080s083,020990s039s041lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 83}
|
11,764
|
Indium In 111 Chloride Sterile
Solution
Rx Only.
Diagnostic - For use only in radiolabeling
OncoScint® CR/OV (Satumomab Pendetide) and
ProstaScint™(Capromab Pendetide).
Radioimmunotherapy - For use only in radiolabel-
ing Zevalin™(Ibritumomab Tiuxetan).
FOR SINGLE USE ONLY
DESCRIPTION:
Indium In 111 Chloride Sterile Solution is indicated
for radiolabeling OncoScint CR/OV and
ProstaScint preparations used for in vivo
diagnostic imaging procedures. It is also indicated
for radiolabeling Zevalin™preparations used for
Radioimmunotherapy procedures. It is supplied as
a sterile, non-pyrogenic solution of Indium In 111
Chloride in 0.05 molar hydrochloric acid. No
carrier has been added to the solution. Each 0.5
milliliter of the solution contains 185
megabequerels (5 millicuries) of indium In 111
chloride at time of calibration (specific activity of
>1.85 GBq/µg Indium; >50 mCi/µg Indium at this
time of calibration). The solution pH is 1.1 to 1.4.
RADIONUCLIDIC PURITY
Indium In 111 is cyclotron produced by the proton
irradiation ((p,2n) reaction) of cadmium Cd 112
enriched target. At time of calibration, it contains
not less than 99.925% indium In 111 and, not
more than 0.075% indium In 114m and zinc Zn 65
combined. At the time of expiration, it contains not
less than 99.85% indium 111 and not more than
0.15% indium In 114m and zinc Zn 65 combined.
No carrier has been added.
RADIOCHEMICAL PURITY
At the time of calibration, the Indium In 111
Chloride Sterile Solution contains not less than
95% of the Indium present as ionic In3+.
CHEMICAL PURITY
Indium In 111 Chloride Sterile Solution is tested
for the following metallic impurities: copper, iron,
cadmium, lead, zinc, nickel, and mercury, and
contains extremely low levels of these metals. The
sum of the individual impurity ratios for the metals
listed is not more than 0.60 ppm.
PHYSICAL CHARACTERISTICS
Indium In 111 decays by electron capture to
cadmium Cd 111 (stable) with a physical half-life
of 67.32 hours (2.81 days)1. Photons useful for
detection and imaging are listed in Table 1.
Table 1. Principal Radiation Emission Data2
EXTERNAL RADIATION
The exposure rate constant for 37 MBq (1 mCi) of
Indium In 111 is 8.3 x 10-4 C/kg/hr (3.21 R/hr) at 1
cm. The specific gamma ray constant for Indium In
111 is 3.21 R/hr-mCi @ 1 cm1. The first half-value
thickness of lead (Pb) is 0.023 cm. A range of
values for the relative attenuation of the radiation
emitted by this radionuclide that results from
interposition of various thicknesses of Pb is shown
in Table 2. For example, the use of 0.834 cm of Pb
will decrease the external radiation exposure by a
factor of about 1000.
Table 2. Indium In 111 Radiation Attenuation by
Lead Shielding1
These estimates of attenuation do not take into
consideration
the
presence
of
longer-lived
contaminants with higher energy photons, namely
Indium In 114m.
1From Radiopharmaceutical Internal Dosimetry
Information Center, Oak Ridge Associated
Universities, Oak Ridge, TN 37831-0117, February
1985.
2Kocher, David C., “Radioactive Decay Data
Tables”, DOE/TIC-11026,115 (1981).
To correct for physical decay of Indium In 111, the
INDIUM In 111
CHLORIDE STERILE
SOLUTION
132
A132I0 R12/2001
Indium In 111 Chloride Sterile Solution
fractions that remain at selected intervals before
and after calibration time are shown in Table 3.
Table 3. Indium In 111 Physical Decay Chart;
Half-life 67.32 hours (2.81 days)
* Calibration time
CLINICAL PHARMACOLOGY
Please refer to the package insert for OncoScint
CR/OV, ProstaScint or Zevalin for this information
on the final drug product.
INDICATIONS AND USAGE
Indium In 111 Chloride Sterile Solution is indicated
for radiolabeling OncoScint CR/OV or ProstaScint
preparations used for in vivo diagnostic imaging
procedures. It is also indicated for radiolabeling
Zevalin
preparations
used
for
Radio-
immunotherapy procedures. Please refer to the
package insert for OncoScint CR/OV, ProstaScint
or Zevalin for information on the final drug product.
CONTRAINDICATIONS
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
WARNINGS
CONTENTS OF THE VIAL OF INDIUM In 111
CHLORIDE SOLUTION ARE INTENDED ONLY TO
BE
USED
AS
AN
INGREDIENT
FOR
RADIOLABELING
ONCOSCINT
CR/OV
OR
PROSTASCINT
FOR
USE
IN
IN
VIVO
DIAGNOSTIC IMAGING PROCEDURES OR TO
BE
USED
AS
AN
INGREDIENT
FOR
RADIOLABELING ZEVALIN™
FOR USE IN
RADIOIMMUNOTHERAPY PROCEDURES, AND
ARE NOT TO BE ADMINISTERED DIRECTLY TO
HUMANS.
PRECAUTIONS
General
Caution must be used to maintain proper
aseptic technique while withdrawing and
transferring contents of the Indium Chloride
solution vial.
Do not use after expiration time and date
indicated on vial label.
Contents of the vial are radioactive and
adequate shielding and handling precautions
must be maintained at all times.
Carcinogenesis, Mutagenesis and Impaired
Fertility
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
Pregnancy Category
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
Nursing Mothers
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
Pediatric Use
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
ADVERSE REACTIONS
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
DOSAGE
AND
ADMINISTRATION
AND
RADIATION DOSIMETRY
Please refer to the package insert for OncoScint
CR/OV, ProstaScint, or Zevalin for this information
on the final drug product.
HOW SUPPLIED
Indium In 111 Chloride Sterile Solution is supplied
in 3 mL vials containing 0.5 mL of solution. It is a
sterile non-pyrogenic solution in 0.05 molar
hydrochloric acid. No carrier is added to the
solution. Each 0.5 mL contains 185 megabequerels
(5 millicuries) of Indium In 111 Chloride at time of
calibration. The pH of the solution is 1.1 to 1.4.
SPECIAL STORAGE AND HANDLING
The contents of the vial are radioactive and
adequate shielding and handling precautions must
be
maintained.
Store
at
controlled
room
temperature 20-25°C (68-77°F)[See USP].
Storage and disposal of Indium In 111 Chloride
Sterile Solution should be controlled in a manner
that is in compliance with the appropriate
regulations of the government agency authorized to
license the use of the radionuclide.
The vial should be kept inside its transportation
shield whenever possible and should be handled
with forceps when contents are being removed.
OncoScint® CR/OV is a registered trademark of
Cytogen Corporation. ProstaScint™is a trademark
of Cytogen Corporation. Zevalin™is a trademark of
IDEC Pharmaceuticals Corporation.
Revised 12/2001
Mallinckrodt Inc.
St. Louis, MO 63134
Professional Services: 1-800-325-3688
Radiation
Mean Percent Per
Disintegration
Mean Energy(keV)
Gamma-2
90.2
171.3
Gamma-3
94.0
245.4
Shield Thickness (Pb) cm
Coefficient of Attenuation
0.023
0.5
0.203
10-1
0.513
10-2
0.834
10-3
1.12
10-4
Hours
Fraction
Remaining
Hours
Fraction
Remaining
-72
2.10
0*
1.00
-60
1.85
6
0.94
-48
1.64
12
0.88
-36
1.45
24
0.78
-24
1.28
36
0.69
-12
1.13
48
0.61
-6
1.06
72
0.48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:04.911314
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/in111mal021902LB.pdf', 'application_number': 19841, 'submission_type': 'SUPPL ', 'submission_number': 3}
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11,765
|
NDA 19-842/S-019
Page 3
MOTRIN® (ibuprofen) Suspension 100 mg/5 mL
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke,
which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for
cardiovascular disease may be at greater risk (See WARNINGS).
• MOTRIN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and
perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (See WARNINGS).
DESCRIPTION - The active ingredient in MOTRIN is ibuprofen, which is a member of the propionic acid group of
nonsteroidal anti-inflammatory drugs (NSAIDs). Ibuprofen is a racemic mixture of [+]S- and [-]R-enantiomers. It is a
white to off-white crystalline powder, with a melting point of 74° to 77°C. It is practically insoluble in water (<0.1 mg/mL),
but readily soluble in organic solvents such as ethanol and acetone. Ibuprofen has a pKa of 4.43±0.03 and an
n-octanol/water partition coefficient of 11.7 at pH 7.4. The chemical name for ibuprofen is (±)-2-(p-isobutylphenyl)
propionic acid. The molecular weight of ibuprofen is 206.28. Its molecular formula is C13H1802 and it has the following
structural formula:
MOTRIN Suspension is a sucrose-sweetened, orange colored, berry flavored suspension containing 100 mg of
ibuprofen in 5 mL (20 mg/mL). Inactive ingredients include: acesulfame-K, citric acid, glycerin, polysorbate 80,
pregelatinized starch, purified water, sodium benzoate, sucrose, xanthan gum, and natural and artificial flavors. It also
may contain one or several of the following colorants: FD&C Red #40, D&C Yellow #10, D&C Red #33, and FD&C Blue
#1.
CLINICAL PHARMACOLOGY
Pharmacodynamics - Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that possesses anti-inflammatory,
analgesic and antipyretic activity. Its mode of action, like that of other NSAIDs, is not completely understood, but may be
related to prostaglandin synthetase inhibition. After absorption of the racemic ibuprofen, the [-]R-enantiomer undergoes
interconversion to the [+]S-form. The biological activities of ibuprofen are associated with the [+]S-enantiomer.
Pharmacokinetics - Ibuprofen is a racemic mixture of [-]R-and [+]S-isomers. In vivo and in vitro studies indicate that
the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly
and incompletely (~60%) interconverted into the active [+]S species in adults. The degree of interconversion in children
is unknown, but is thought to be similar. The [-]R-isomer serves as a circulating reservoir to maintain levels of active
drug. Ibuprofen is well absorbed orally, with less than 1% being excreted in the urine unchanged. It has a biphasic
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 4
elimination time curve with a plasma half-life of approximately 2 hours. Studies in febrile children have established the
dose-proportionality of 5 and 10 mg/kg doses of ibuprofen. Studies in adults have established the dose-proportionality of
ibuprofen as a single oral dose from 50 to 600 mg for total drug and up to 1200 mg for free drug.
Absorption - In vivo studies indicate that ibuprofen is well absorbed orally from the suspension formulation, with peak
plasma levels usually occurring within 1 to 2 hours (see Table 1).
Table 1
Pharmacokinetic Parameters of Ibuprofen Suspension
[Mean values (% coefficient of variation)]
Dose
200mg
(2.8mg/kg) in
Adults
10mg/kg in Febrile
Children
Formulation
Suspension
Suspension
Number of Patients
24
18
AUCinf (µg•h/mL)
64
(27%)
155
(24%)
Cmax (µg/mL)
19
(22%)
55
(23%)
Tmax (h)
0.79
(69%)
0.97
(57%)
CI/F(mL/h/kg)
45.6
(22%)
68.6
(22%)
Legend:
AUCinf = Area-under-the-curve to infinity
Tmax = Time-to-peak plasma concentration
Cmax = Peak plasma concentration
Cl/F = Clearance divided by fraction at drug absorbed
Antacids - A bioavailability study in adults has shown that there was no interference with the absorption of ibuprofen
when given in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide.
H-2 Antagonists – In studies with human volunteers, coadministration of cimetidine or ranitidine with ibuprofen had no
substantive effect on ibuprofen serum concentrations.
Food Effects - Absorption is most rapid when MOTRIN is given under fasting conditions. Administration of MOTRIN
Suspension with food affects the rate but not the extent of absorption. When taken with food, Tmax is delayed by
approximately 30 to 60 minutes, and peak levels are reduced by approximately 30 to 50%.
Distribution - Ibuprofen, like most drugs of its class, is highly protein bound (>99% bound at 20 µg/mL). Protein binding
is saturable and at concentrations >20 µg/mL binding is non-linear. Based on oral dosing data there is an age- or fever-
related change in volume of distribution for ibuprofen. Febrile children <11 years old have a volume of approximately 0.2
L/kg while adults have a volume of approximately 0.12 L/kg. The clinical significance of these findings is unknown.
Metabolism - Following oral administration, the majority of the dose was recovered in the urine within 24 hours as the
hydroxy-(25%) and carboxypropyl-(37%) phenylpropionic acid metabolites. The percentages of free and conjugated
ibuprofen found in the urine were approximately 1% and 14%, respectively. The remainder of the drug was found in the
stool as both metabolites and unabsorbed drug.
Elimination - Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually
complete 24 hours after the last dose. It has a biphasic plasma elimination time curve with a half-life of approximately
2.0 hours. There is no difference in the observed terminal elimination rate or half-life between children and adults,
however, there is an age-or fever-related change in total clearance. This suggests that the observed change in
clearance is due to changes in the volume of distribution of ibuprofen (see Table 1 for Cl/F values).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 5
Clinical Studies - Controlled clinical trials comparing doses of 5 and 10 mg/kg ibuprofen suspension and 10-15 mg/kg
of acetaminophen elixir have been conducted in children 6 months to 12 years of age with fever primarily due to viral
illnesses. In these studies there were no differences between treatments in fever reduction for the first hour and
maximum fever reduction occurred between 2 and 4 hours. Response after 1 hour was dependent on both the level of
temperature elevation as well as the treatment. In children with baseline temperatures at or below 102.5°F both
ibuprofen doses and acetaminophen were equally effective in their maximum effect. In children with temperatures above
102.5°F, the ibuprofen 10 mg/kg dose was more effective. By 6 hours, children treated with ibuprofen 5mg/kg tended to
have recurrence of fever, whereas children treated with ibuprofen 10 mg/kg still had significant fever reduction at 8
hours. In control groups treated with 10 mg/kg acetaminophen, fever reduction resembled that seen in children treated
with 5 mg/kg of ibuprofen, with the exception that temperature elevation tended to return 1-2 hours earlier.
In patients with primary dysmenorrhea, ibuprofen has been shown to reduce elevated levels of prostaglandin activity in
the menstrual fluid and to reduce testing and active intrauterine pressure, as well as the frequency of uterine
contractions. The probable mechanism of action is to inhibit prostaglandin synthesis rather than simply to provide
analgesia.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of MOTRIN Suspension and other treatment options before deciding
to use MOTRIN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
In Pediatric Patients, MOTRIN Suspension is indicated:
•For reduction of fever in patients aged 6 months up to 2 years of age.
•For relief of mild to moderate pain in patients aged 6 months up to 2 years of age.
•For relief of signs and symptoms of juvenile arthritis.
In Adults, MOTRIN is indicated:
•For treatment of primary dysmenorrhea.
•For relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Since there have been no controlled trials to demonstrate whether there is any beneficial effect or harmful interaction
with the use of ibuprofen in conjunction with aspirin, the combination cannot be recommended. (See PRECAUTIONS –
Drug Interactions).
CONTRAINDICATIONS
MOTRIN Suspension is contraindicated in patients with known hypersensitivity to ibuprofen.
MOTRIN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions
after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDS have been reported in
such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).
MOTRIN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass
graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an
increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk
factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 6
with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients
should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should
be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic
events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including MOTRIN Suspension, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop
diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including MOTRIN
Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored
closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. MOTRIN Suspension should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including MOTRIN Suspension, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be
fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with
NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAAID therapy, is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of
patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.
However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal
bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a
greater than 10-fold risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors
that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status.
Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be
taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose
should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms
of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious
GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is
ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal
toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug
may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow,
which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 7
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of MOTRIN Suspension in patients with
advanced renal disease. Therefore, treatment with MOTRIN Suspension is not recommended in these patients with
advanced renal disease. If MOTRIN Suspension therapy must be initiated, close monitoring of the patient’s renal
function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to MOTRIN
Suspension. Motrin Suspension should not be given to patients with the aspirin triad. This symptom complex typically
occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal
bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS – Preexisting
Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including MOTRIN Suspension, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of
hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, MOTRIN should be avoided because it may cause premature closure of the
ductus arteriosus.
PRECAUTIONS
General
MOTRIN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of MOTRIN Suspension in reducing fever and inflammation may diminish the utility of
these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including MOTRIN
Suspension. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing
therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been
reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic
reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal
outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred,
should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with MOTRIN
Suspension. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur
(e.g., eosinophilia, rash, etc.), MOTRIN Suspension should be discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 8
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including MOTRIN Suspension. This may be due to fluid
retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-
term treatment with NSAIDs, including MOTRIN Suspension, should have their hemoglobin or hematocrit checked if
they exhibit any signs or symptoms of anemia.
In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than previously
reported. Decrease in hemoglobin of 1 gram or more was observed in 17.1% of 193 patients on 1600 mg ibuprofen
daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen daily (rheumatoid arthritis). Positive
stool occult blood tests and elevated serum creatinine levels were also observed in these studies.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin,
their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving MOTRIN
Suspension who may be adversely affected by alterations in platelet function, such as those with coagulation disorders
or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma
has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm,
between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients,
MOTRIN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used
with caution in patients with preexisting asthma.
Aseptic Meningitis
Aseptic meningitis, with fever and coma, has been observed on rare occasions in patients on ibuprofen therapy.
Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue
diseases, it has been reported in patients who do not have an underlying chronic disease.
Diabetics
MOTRIN Suspension contains 0.3 g sucrose and 1.6 calories per mL, or 1.5 g sucrose and 8 calories per teaspoon,
which should be taken into consideration when treating diabetic patients with this product.
Information for Patients:
Patients should be informed of the following information before initiating therapy with an NSAID and
periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.
1. MOTRIN Suspension, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may
result in hospitalization, and even death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of
speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should
be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. MOTRIN Suspension, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as
ulcers and bleeding, which may result in hospitalization or even death. Although serious GI tract ulcerations
and bleeding can occur without warning symptoms, patients should be alert for signs and symptoms of
ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms
including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance
of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 9
3. MOTRIN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS,
and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur
without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other
signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative
signs
or
symptoms.
Patients
should
be
advised
to
stop
the
drug
immediately
if
they
develop
any
type
of
rash
or
contact
their
physicians
as
soon
as
possible.
4. Patients should promptly reports signs and symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritis, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the
face or throat). If these occur, patients should be instructed to seek immediate emergency help (see
WARNINGS).
7. In late pregnancy, as with other NSAIDs, MOTRIN Suspension should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for
signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry
profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic
manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, MOTRIN Suspension
should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be
given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
Aspirin
As with other NSAIDs, concomitant administration of IBUPROFEN and aspirin is not generally recommended
because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as post marketing observations, have shown that MOTRIN Suspension can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for
signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of
eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of
lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed
to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when MOTRIN and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation
before use of such concurrent therapy.)
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may
indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered
concomitantly with methotrexate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 10
Warfarin
Several short-term controlled studies failed to show that MOTRIN tablets significantly affected prothrombin times or a
variety of other clotting factors when administered to individuals on warfarin-type anticoagulants. However, because
bleeding has been reported when MOTRIN tablets and other NSAIDs have been administered to patients on
warfarin-type anticoagulants, the physician should be cautious when administering MOTRIN tablets to patients on
anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs
together have a risk of serious GI bleeding higher than users of either drug alone.
Pregnancy
Teratogenic Effects – Pregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities.
However, animal reproduction studies are not always predictive of human response. There are no adequate and
well-controlled studies in pregnant women. Motrin should be used in pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of
ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of
dystocia, delayed parturition, and decreased pup survival occurred. The effects of MOTRIN Suspension on labor and
delivery in pregnant women are unknown. Therefore, administration of MOTRIN Suspension is not recommended
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants from MOTRIN suspension, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness of MOTRIN Suspension in pediatric patients below the age of 6 months have not been
established (see CLINICAL PHARMACOLOGY - Clinical Studies). Dosing of MOTRIN Suspension in children 6 months
or older should be guided by their body weight (see DOSAGE AND ADMINISTRATION).
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 11
ADVERSE REACTIONS
In patients taking MOTRIN or other NSAIDs, the most frequently reported adverse experiences occurring in
approximately 1-10% of patients are: Abnormal renal function, anemia, dizziness, edema, elevated liver
enzymes, fluid retention, gastrointestinal experiences (including abdominal pain, bloating, constipation, diarrhea,
dyspepsia,
epigastric
pain,
flatulence,
heartburn,
nausea,
vomiting),
headaches,
increased
bleeding
time, nervousness, pruritus, rashes (including maculopapular) and tinnitus.
Additional adverse experiences reported occasionally include:
Body as a whole -
fever, infection, sepsis
Cardiovascular system -
congestive heart failure in patients with marginal cardiac function, hypertension,
tachycardia, syncope
Digestive system -
dry mouth, duodenitits, esophagitis, gastric or duodenal ulcer with bleeding and/or
perforation, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis,
jaundice, melena, rectal bleeding
Hemic and lymphatic system -
ecchymosis, eosinophilia, leukopenia, purpura, stomatitis, thrombocytopenia
Metabolic and nutritional -
weight changes
Nervous system -
anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, paresthesia, somnolence, tremors, vertigo
Respiratory system -
asthma, dyspnea
Skin and appendages -
alopecia, photosensitivity, sweat
Special senses -
blurred vision
Urogenital system -
cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, acute
renal failure in patients with pre-existing significantly impaired renal function
Other adverse reactions, which occur rarely are:
Body as a whole -
anaphylactic reactions, anaphylactoid reactions, appetite changes,
Cardiovascular system -
arrhythmia,
cerebrovascular
accident,
hypotension,
myocardial
infarction,
palpitations, vasculitis
Digestive system -
eructation, gingival ulcer, hepatorenal syndrome, liver necrosis, liver failure,
pancreatitis
Hemic and lymphatic system -
agranulocystosis,
hemolytic
anemia,
aplastic
anemia,
lymphadenopathy,
neutropenia, pancytopenia
Metabolic and nutritional -
hyperglycemia
Nervous system -
convulsions, coma, emotional lability hallucinations, aseptic meningitis
Respiratory -
apnea, respiratory depression, pneumonia, rhinitis
Skin and appendages -
angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis,
Stevens Johnson syndrome, urticaria, vesiculobullous eruptions
Special senses -
amblyopia (blurred and/or diminished vision, scotomata and/or changes in color
vision), conjunctivitis, dry eyes, hearing impairment
Urogenital-
azotemia, decreased creatinine clearance, glomerulitis, renal papillary necrosis,
tubular necrosis
OVERDOSAGE
The toxicity of ibuprofen overdose is dependent upon the amount of drug ingested and the time elapsed since ingestion,
though individual response may vary, which makes it necessary to evaluate each case individually. Although
uncommon, serious toxicity and death have been reported in the medical literature with ibuprofen overdosage. The most
frequently reported symptoms of ibuprofen overdose include abdominal pain, nausea, vomiting, lethargy and
drowsiness. Other central nervous system symptoms include headache, tinnitus, CNS depression and seizures.
Metabolic acidosis, coma, acute renal failure and apnea (primarily in very young children) may rarely occur.
Cardiovascular toxicity, including hypotension, bradycardia, tachycardia and atrial fibrillation, also have been reported.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 12
The treatment of acute ibuprofen overdose is primarily supportive. Management of hypotension, acidosis and
gastrointestinal bleeding may be necessary. In cases of acute overdose, the stomach should be emptied through
ipecac-induced emesis or lavage. Emesis is most effective if initiated within 30 minutes of ingestion.
Orally administered activated charcoal may help in reducing the absorption and reabsorption of ibuprofen.
In children, the estimated amount of ibuprofen ingested per body weight may be helpful to predict the potential for
development of toxicity although each case must be evaluated. Ingestion of less than 100 mg/kg is unlikely
to produce toxicity. Children ingesting 100 to 200 mg/kg may be managed with induced emesis and a minimal
observation time of four hours. Children ingesting 200 to 400 mg/kg of ibuprofen should have immediate gastric
emptying and at least four hours observation in a health care facility. Children ingesting greater than 400 mg/kg
require immediate medical referral, careful observation and appropriate supportive therapy. Ipecac-induced emesis is
not recommended in overdoses greater than 400 mg/kg because of the risk for convulsions and the potential for
aspiration of gastric contents.
In adult patients the history of the dose reportedly ingested does not appear to be predictive of toxicity. The need for
referral and follow-up must be judged by the circumstances at the time of the overdose ingestion. Symptomatic
adults should be carefully evaluated, observed and supported.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of MOTRIN Suspension and other treatment options before
deciding to use MOTRIN Suspension. Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with MOTRIN Suspension, the dose and frequency should be adjusted to
suit an individual patient’s needs.
PEDIATRIC PATIENTS
Fever reduction: For reduction of fever in children, 6 months up to 2 years of age, the dosage should be adjusted on
the basis of the initial temperature level (see CLINICAL PHARMACOLOGY). The recommended dose is 5 mg/kg if the
baseline temperature is less than 102.5ºF, or 10 mg/kg if the baseline temperature is 102.5ºF or greater. The duration of
fever reduction is generally 6 to 8 hours. The recommended maximum daily dose is 40 mg/kg.
Analgesia: For relief of mild to moderate pain in children 6 months up to 2 years of age, the recommended dosage is
10 mg/kg, every 6 to 8 hours. The recommended maximum daily dose is 40 mg/kg. Doses should be given so as not to
disturb the child's sleep pattern.
Juvenile Arthritis: The recommended dose is 30 to 40 mg/kg/day divided into three to four doses (see Individualization
of Dosage). Patients with milder disease may be adequately treated with 20 mg/kg/day.
In patients with juvenile arthritis, doses above 50 mg/kg/day are not recommended because they have not been studied
and doses exceeding the upper recommended dose of 40 mg/kg/day may increase the risk of causing serious adverse
events. The therapeutic response may require from a few days to several weeks to be achieved. Once a clinical effect
is obtained, the dosage should be lowered to the smallest dose of MOTRIN needed to maintain adequate control of
symptoms.
Pediatric patients receiving doses above 30 mg/kg/day or if abnormal liver function tests have occurred with previous
NSAID treatments should be carefully followed for signs and symptoms of early liver dysfunction.
ADULTS
Primary Dysmenorrhea: For the treatment of primary dysmenorrhea, beginning with the earliest onset of such pain,
MOTRIN Suspension should be given in a dose of 400 mg every 4 hours, as necessary, for the relief of pain.
Rheumatoid arthritis and osteoarthritis: Suggested dosage: 1200-3200 mg daily (300 mg q.i.d. or 400 mg, 600 mg or
800 mg t.i.d. or q.i.d.). Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 13
although in well-controlled clinical trials patients on 3200 mg did not show a better mean response in terms of efficacy.
Therefore, when treating patients with 3200 mg/day, the physician should observe sufficient increased clinical benefits
to offset potential increased risk.
Individualization of Dosage: The dose of MOTRIN Suspension should be tailored to each patient, and may be
lowered or raised from the suggested doses depending on the severity of symptoms either at time of initiating drug
therapy or as the patient responds or fails to respond.
One fever study showed that, after the initial dose of MOTRIN Suspension, subsequent doses may be lowered and still
provide adequate fever control.
In a situation when low fever would require the MOTRIN Suspension 5 mg/kg dose in a child with pain, the dose that will
effectively treat the predominant symptom should be chosen.
In chronic conditions, a therapeutic response to MOTRIN Suspension therapy is sometimes seen in a few days to a
week, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose
should be reviewed and adjusted as required.
Patients with rheumatoid arthritis seem to require higher doses than do patients with osteoarthritis. The smallest dose
of MOTRIN Suspension that yields acceptable control should be employed.
MOTRIN Suspension may be used in combination with gold salts and/or corticosteroids.
HOW SUPPLIED
MOTRIN® (ibuprofen) Suspension, 100 mg/5 mL
Orange-colored, berry- flavored suspension
- Bottles of 120 mL – NDC 0045-XXXX-04
- Bottles of 480 mL – NDC 0045-XXXX-16
Shake well before using. Store at controlled room temperature [15º to 30ºC (59º to 86ºF)]
Caution: Federal Law prohibits dispensing without prescription.
McNEIL CONSUMER & SPECIALTY PHARMACEUTICALS
DIVISION OF McNEIL-PPC, INC.
FORT WASHINGTON, PA 19034-USA
January 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 14
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 15
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-842/S-019
Page 16
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019842s019lbl.pdf', 'application_number': 19842, 'submission_type': 'SUPPL ', 'submission_number': 19}
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NDA 19-845/S-017
Page 3
Betoptic S
(betaxolol HCL)
0.25% as base
DESCRIPTION: BETOPTIC S Ophthalmic Suspension 0.25% contains betaxolol
hydrochloride, a cardioselective beta-adrenergic receptor blocking agent, in a sterile resin
suspension formulation. Betaxolol hydrochloride is a white, crystalline powder, with a molecular
weight of 343.89. The chemical structure is presented below:
[Structure]
Empirical Formula:
C18H29N03•HCl
Chemical Name:
(+)-1-[p-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(isopropylamino)-2-propanol hydrochloride.
Each mL of BETOPTIC S® Ophthalmic Suspension contains: Active: betaxolol HCl 2.8 mg
equivalent to 2.5 mg of betaxolol base. Preservative: benzalkonium chloride 0.01%. Inactive:
Mannitol, Poly(Styrene-Divinyl Benzene) sulfonic acid, Carbomer 934P, edetate disodium,
hydrochloric acid or sodium hydroxide (to adjust pH) and purified water.
CLINICAL PHARMACOLOGY: Betaxolol HCl, a cardioselective (beta- l-adrenergic) receptor
blocking agent, does not have significant membrane-stabilizing (local anesthetic) activity and is
devoid of intrinsic sympathomimetic action. Orally administered beta-adrenergic blocking agents
reduce cardiac output in healthy subjects and patients with heart disease. In patients with severe
impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the
sympathetic stimulatory effect necessary to maintain adequate cardiac function.
When instilled in the eye, BETOPTIC S® Ophthalmic Suspension 0.25% has the action of
reducing elevated intraocular pressure, whether or not accompanied by glaucoma. Ophthalmic
betaxolol has minimal effect on pulmonary and cardiovascular parameters.
Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP,
the greater the likelihood of optic nerve damage and visual field loss. Betaxolol has the action of
reducing elevated as well as normal intraocular pressure and the mechanism of ocular hypotensive
action appears to be a reduction of aqueous production as demonstrated by tonography and
aqueous fluorophotometry. The onset of action with betaxolol can generally be noted within 30
minutes and the maximal effect can usually be detected 2 hours after topical administration. A
single dose provides a 12-hour reduction in intraocular pressure.
In controlled, double-masked studies, the magnitude and duration of the ocular hypotensive effect
of BETOPTIC S® Ophthalmic Suspension 0.25% and BETOPTIC® Ophthalmic Solution 0.5%
were clinically equivalent. BETOPTIC S® Suspension was significantly more comfortable than
BETOPTIC Solution.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-017
Page 4
Ophthalmic betaxolol solution at 1% (one drop in each eye) was compared to placebo in a
crossover study challenging nine patients with reactive airway disease. Betaxolol HCl had no
significant effect on pulmonary function as measured by FEV1, Forced Vital Capacity (FVC),
FEV1/FVC and was not significantly different from placebo. The action of isoproterenol, a beta
stimulant, administered at the end of the study was not inhibited by ophthalmic betaxolol.
No evidence of cardiovascular beta adrenergic-blockade during exercise was observed with
betaxolol in a double-masked, crossover study in 24 normal subjects comparing ophthalmic
betaxolol and placebo for effects on blood pressure and heart rate.
INDICATIONS AND USAGE: BETOPTIC S Ophthalmic Suspension 0.25% has been shown
to be effective in lowering intraocular pressure and may be used in patients with chronic
open-angle glaucoma and ocular hypertension. It may be used alone or in combination with other
intraocular pressure lowering meditations.
CONTRAINDICATIONS: Hypersensitivity to any component of this product BETOPTIC S®
Ophthalmic Suspension 0.25% is contraindicated in patients with sinus bradycardia, greater than a
first degree atrioventricular block, cardiogenic shock, or patients with overt cardiac failure.
WARNING: FOR TOPICAL OPHTHALMIC USE ONLY. Topically applied beta-adrenergic
blocking agents may be absorbed systemically. The same adverse reactions found with systemic
administration of beta-adrenergic blocking agents may occur with topical administration. For
example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm
in patients with asthma, and rarely death in association with cardiac failure, have been reported
with topical application of beta-adrenergic blocking agents.
BETOPTIC S® Ophthalmic Suspension 0.25% has been shown to have a minor effect on heart
rate and blood pressure in clinical studies. Caution should be used in treating patients with a
history of cardiac failure or heartblock. Treatment with BETOPTIC S Ophthalmic Suspension
0.25% should be discontinued at the first signs of cardiac failure.
PRECAUTIONS:
General:
Diabetes Mellitus. Beta-adrenergic blocking agents should be administered with caution in
patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile
diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor
blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis. Beta-adrenergic blocking agents may mask certain clinical signs (e.g.,
tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be
managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents, which might
precipitate a thyroid storm.
Muscle Weakness. Beta-adrenergic blockade has been reported to potentiate muscle weakness
consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-017
Page 5
Major Surgery. Consideration should be given to the gradual withdrawal of beta-adrenergic
blocking agents prior to general anesthesia because of the reduced ability of the heart to respond
to beta-adrenergically mediated sympathetic reflex stimuli.
Pulmonary. Caution should be exercised in the treatment of glaucoma patients with excessive
restriction of pulmonary function. There have been reports of asthmatic attacks and pulmonary
distress during betaxolol treatment. Although rechallenges of some such patients with ophthalmic
betaxolol has not adversely affected pulmonary function test results, the possibility of adverse
pulmonary effects in patients sensitive to beta blockers cannot be ruled out.
Information for Patients: Do not touch dropper tip to any surface, as this may contaminate the
contents. Do not use with contact lenses in eyes.
Drug Interactions: Patients who are receiving a beta-adrenergic blocking agent orally and
BETOPTIC S Ophthalmic Suspension 0.25% should be observed for a potential additive effect
either on the intraocular pressure or on the known systemic effects of beta blockade.
Close observation of the patient is recommended when a beta blocker is administered to patients
receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects
and the production of hypotension and/or bradycardia.
Betaxolol is an adrenergic blocking agent; therefore, caution should be exercised in patients using
concomitant adrenergic psychotropic drugs.
Risk from anaphylactic reaction: While taking beta-blockers, patients with a history of atopy or
a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated
accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be
unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
Ocular: In patients with angle-closure glaucoma, the immediate treatment objective is to reopen
the angle by constriction of the pupil with a miotic agent. Betaxolol has little or no effect on the
pupil. When BETOPTIC S Ophthalmic Suspension 0.25% is used to reduce elevated intraocular
pressure in angle-closure glaucoma, it should be used with a miotic and not alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime studies with betaxolol HCl
have been completed in mice at oral doses of 6, 20 or 60 mg/kg/day and in rats at 3, 12 or 48
mg/kg/day; betaxolol HCl demonstrated no carcinogenic effect. Higher dose levels were not
tested.
In a variety of in vitro and in vivo bacterial and mammalian cell assays, betaxolol HCl was
nonmutagenic.
Pregnancy:
Pregnancy Category C. Reproduction, teratology, and peri- and postnatal studies have been
conducted with orally administered betaxolol HCl in rats and rabbits. There was evidence of drug
related postimplantation loss in rabbits and rats at dose levels above 12 mg/kg and 128 mg/kg,
respectively. Betaxolol HCl was not shown to be teratogenic, however, and there were no other
adverse effects on reproduction at subtoxic dose levels. There are no adequate and well-controlled
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-017
Page 6
studies in pregnant women. BETOPTIC S® Ophthalmic Suspension should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether betaxolol HCl is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when BETOPTIC S
Ophthalmic Suspension 0.25% is administered to nursing women.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: No overall differences in safety or effectiveness have been observed between
elderly and younger patients.
ADVERSE REACTIONS:
Ocular: In clinical trials, the most frequent event associated with the use of BETOPTIC S®
Ophthalmic Suspension 0.25% has been transient ocular discomfort. The following other
conditions have been reported in small numbers of patients: blurred vision, corneal punctate
keratitis, foreign body sensation, photophobia, tearing, itching, dryness of eyes, erythema,
inflammation, discharge, ocular pain, decreased visual acuity and crusty lashes.
Additional medical events reported with other formulations of betaxolol include allergic reactions,
decreased corneal sensitivity, corneal punctate staining which may appear in dendritic formations,
edema and anisocoria.
Systemic: Systemic reactions following administration of BETOPTIC S® Ophthalmic
Suspension 0.25% or BETOPTIC Ophthalmic Solution 0.5% have been rarely reported. These
include:
Cardiovascular: Bradycardia, heart block and congestive failure.
Pulmonary: Pulmonary distress characterized by dyspnea, bronchospasm, thickened bronchial
secretions, asthma and respiratory failure.
Central Nervous System: Insomnia, dizziness, vertigo, headaches, depression, lethargy, and
increase in signs and symptoms of myasthenia gravis.
Other: Hives, toxic epidermal necrolysis, hair loss, and glossitis. Perversions of taste and smell
have been reported.
OVERDOSAGE: No information is available on overdosage of humans. The oral LD50 of the
drug ranged from 350-920 mg/kg in mice and 860-1050 mg/kg in rats. The symptoms which
might be expected with an overdose of a systemically administered beta-1 -adrenergic receptor
blocking agent are bradycardia, hypotension and acute cardiac failure.
A topical overdose of BETOPTIC S® Ophthalmic Suspension 0.25% may be flushed from the
eye(s) with warm tap water.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-017
Page 7
DOSAGE AND ADMINISTRATION: The recommended dose is one to two drops of
BETOPTIC S® Ophthalmic Suspension 0.25% in the affected eye(s) twice daily. In some
patients, the intraocular pressure lowering responses to BETOPTIC S® may require a few weeks
to stabilize. As with any new medication, careful monitoring of patients is advised.
If the intraocular pressure of the patient is not adequately controlled on this regimen, concomitant
therapy with pilocarpine and other miotics, and/or epinephrine and/or carbonic anhydrase
inhibitors can be instituted.
HOW SUPPLIED: BETOPTIC S® Ophthalmic Suspension 0.25% is supplied as follows: 2.5, 5,
10 and 15 ml in plastic ophthalmic DROP-TAINER dispensers.
2.5 mL: NDC 0065-0246-20
10 mL: NDC 0065-0246-10
5 mL: NDC 0065-0246-05
15 mL: NDC 0065-0246-15
STORAGE: Store upright at room temperature. Shake well before using.
Rx Only
U.S. Patents No. 4,911,920
2002 Alcon Laboratories, Inc.
Alcon
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
Printed In U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:46:05.235660
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19845slr017_betopic_lblo.pdf', 'application_number': 19845, 'submission_type': 'SUPPL ', 'submission_number': 17}
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11,763
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ZOLOFT®
(sertraline hydrochloride)
Tablets and Oral Concentrate
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
ZOLOFT or any other antidepressant in a child, adolescent, or young adult must balance this
risk with the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24; there was a
reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in
the risk of suicide. Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening, suicidality, or unusual
changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. ZOLOFT is not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD). (See
Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and
Precautions: Pediatric Use)
DESCRIPTION
ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. The empirical formula C17H17NCl2HCl is represented by the following structural
formula:
1
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
tructu ral
for
mula
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and
isopropyl alcohol, and sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic
calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue
#1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C
Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch
glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.
ZOLOFT oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains
sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following
inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for
Patients and DOSAGE AND ADMINISTRATION).
2
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal
uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that
sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also
suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has
only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have
shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine
receptors; antagonism of such receptors has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to down regulate brain norepinephrine
receptors, as has been observed with other drugs effective in the treatment of major depressive
disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to
200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5
to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about
26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should
be achieved after approximately one week of once-daily dosing. Linear dose-proportional
pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under
the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range
of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately
two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to
200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to
an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the
oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence
intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for
Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were
studied in subjects administered a single dose with and without food. For the tablet, AUC was
slightly increased when drug was administered with food but the Cmax was 25% greater, while
the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours
with food.
Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway
of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological
testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
3
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two
healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About
40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline
was not detectable in the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax
and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and
day 14.
Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of
major depressive disorder or obsessive-compulsive disorder. Patients included both males
(N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated
up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of
sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old
group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely
attributable to patients with lower body weights. No gender associated differences were
observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of
age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about
22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency
than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower
body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).
Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group
of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to
3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can
affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who
received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
4
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold
greater compared to age-matched volunteers with no hepatic impairment. There were no
significant differences in plasma protein binding observed between the two groups. The effects
of sertraline in patients with moderate and severe hepatic impairment have not been studied. The
results suggest that the use of sertraline in patients with liver disease must be approached with
caution. If sertraline is administered to patients with liver impairment, a lower or less frequent
dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is
a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min),
moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment
(N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no
renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by
renal impairment (see PRECAUTIONS).
Clinical Trials
Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive
disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III
criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.
Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.
Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open
treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to
continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on
placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the
basis of sex.
Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of
OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with
mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score
ranging from 23 to 25.
5
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 4 points on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of
approximately 6 points on the YBOCS total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day;
the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean
reduction of approximately 7 points on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week,
multicenter, placebo-controlled, parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at
doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then
titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose
for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in
this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS
total score which was significantly greater than the 3 unit reduction for placebo patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness
on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during
a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the single-blind
phase was defined as a decrease in the YBOCS score of 25% compared to baseline and a CGI
I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the
double-blind phase was defined as the following conditions being met (on three consecutive
visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by 5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by one point; and (3) worsening of
the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient
clinical response indicated a worsening of the patient’s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment
experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical
response over the subsequent 28 weeks compared to those receiving placebo. This pattern was
demonstrated in male and female subjects.
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Reference ID: 3626722
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was
demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients
who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day
and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be
significantly more effective than placebo on change from baseline in panic attack frequency and
on the Clinical Global Impression Severity of Illness and Global Improvement scores. The
difference between ZOLOFT and placebo in reduction from baseline in the number of full panic
attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack
frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for
discontinuation due to relapse or insufficient clinical response. Response during the open phase
was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during
the double-blind phase was defined as the following conditions being met on three consecutive
visits: (1) CGI-I 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic
attacks greater than at baseline. Insufficient clinical response indicated a worsening of the
patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation
due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those
receiving placebo. This pattern was demonstrated in male and female subjects.
Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of
PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult
outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients
was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated)
had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the
first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical
response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and
151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
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Reference ID: 3626722
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For current labeling information, please visit https://www.fda.gov/drugsatfda
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion,
avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES)
which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly
more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the
Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two
additional placebo-controlled PTSD trials, the difference in response to treatment between
patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One
of these additional studies was conducted in patients similar to those recruited for Studies 1 and
2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in
these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on
sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a
significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women,
regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect
in the relatively smaller number of men in these studies. The clinical significance of this
apparent gender interaction is unknown at this time. There was insufficient information to
determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during
a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of
ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response
during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved),
and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-
blind phase was defined as the following conditions being met on two consecutive visits: (1)
CGI-I 3; (2) CAPS-2 score increased by 30% and by 15 points relative to baseline; and (3)
worsening of the patient's condition in the investigator's judgment. Patients receiving continued
ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and female
subjects.
Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment
of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose
trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R
criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as
Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV
criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized
luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD
symptoms for these patients was approximately 10.5 years in both studies. Patients on oral
contraceptives were excluded from these trials; therefore, the efficacy of sertraline in
combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated
instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and
includes assessments for mood, physical symptoms, and other symptoms. Other efficacy
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assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical
Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients; ZOLOFT treatment was initiated at 50 mg/day
and administered daily throughout the menstrual cycle. In subsequent cycles, patients were
dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean
dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual
cycle was significantly more effective than placebo on change from baseline to endpoint on the
DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at
endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day
in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset
of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal
phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated
to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the
remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in the late luteal phase of the menstrual cycle was significantly more effective than
placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these
studies.
Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety
disorder (also known as social phobia) was established in two multicenter placebo-controlled
studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day)
to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was
assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered
instrument that measures fear, anxiety and avoidance of social and performance situations, and
by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement
(CGI-I) criterion of CGI-I 2 (very much or much improved). ZOLOFT was statistically
significantly more effective than placebo as measured by the LSAS and the percentage of
responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200
mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale
(BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic
response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of
phobic avoidance and distress, and (c) the CGI-I responder criterion of 2. ZOLOFT was
shown to be statistically significantly more effective than placebo as measured by the BSPS total
score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
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Reference ID: 3626722
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Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.
There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had
responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled
trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution
of placebo for up to 24 weeks of observation for relapse. Relapse was defined as 2 point
increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower relapse rate over this 24
week study than patients randomized to placebo substitution.
INDICATIONS AND USAGE
Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment
of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to
eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it
should include at least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately
studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended
periods should be reevaluated periodically (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the
DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or
significantly interfere with social or occupational functioning.
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Reference ID: 3626722
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The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III
or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during
a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a
period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT
for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see
Clinical Trials under CLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated
heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or
smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality)
or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of
dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the
treatment of posttraumatic stress disorder in adults.
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Reference ID: 3626722
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The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week
placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R
category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual
or threatened death or serious injury, or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28
weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled
trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled
trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III
R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective
lability, and persistent anger or irritability. Other features include decreased interest in activities,
difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle
pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and
remit within a few days following onset of menses; the disturbance markedly interferes with
work or school or with usual social activities and relationships with others. In making the
diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated
by treatment with an antidepressant.
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The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two
placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as
defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of
social or performance situations involving exposure to unfamiliar people or possible scrutiny by
others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social
situation almost always provokes anxiety and feared social or performance situations are avoided
or else are endured with intense anxiety or distress. In addition, patients recognize that the fear
is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is
associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder
for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-
controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically re
evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
The use of MAOIs intended to treat psychiatric disorders with ZOLOFT or within 14 days of
stopping treatment with ZOLOFT is contraindicated because of an increased risk of serotonin
syndrome. The use of ZOLOFT within 14 days of stopping an MAOI intended to treat
psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Starting ZOLOFT in a patient who is being treated with MAOIs such as linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
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Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young
adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to
placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of
9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in
adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable
variation in risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These risk differences
(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided
in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
Increases Compared to Placebo
18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
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No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZOLOFT
should be written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
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treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that ZOLOFT is not approved for use in treating bipolar
depression.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has
been reported with SNRIs and SSRIs, including ZOLOFT, alone but particularly with
concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that
impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity,
myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin
syndrome.
The concomitant use of ZOLOFT with MAOIs intended to treat psychiatric disorders is
contraindicated. ZOLOFT should also not be started in a patient who is being treated with
MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that
provided information on the route of administration involved intravenous administration in the
dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by
other routes (such as oral tablets or local tissue injection) or at lower doses. There may be
circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or
intravenous methylene blue in a patient taking ZOLOFT. ZOLOFT should be discontinued
before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND
ADMINISTRATION).
If concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is
clinically warranted, patients should be made aware of a potential increased risk for serotonin
syndrome, particularly during treatment initiation and dose increases.
Treatment with ZOLOFT and any concomitant serotonergic agents should be discontinued
immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many
antidepressant drugs including Zoloft may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
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PRECAUTIONS
General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred
in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.
Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline
for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight
loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued
for weight loss.
Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients
were excluded from clinical studies during the product’s premarket testing. No seizures were
observed among approximately 3000 patients treated with ZOLOFT in the development program
for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of
age) exposed during the development program for obsessive-compulsive disorder experienced
seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder, none of whom were
receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in
patients with a seizure disorder.
Discontinuation of Treatment with ZOLOFT
During marketing of ZOLOFT and other SSRIs and SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and
hypomania. While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with ZOLOFT.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
SSRIs and SNRIs, including ZOLOFT, may increase the risk of bleeding events ranging from
ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening
hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants or other drugs known to affect platelet function may add to this risk. Case
reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
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ZOLOFT and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean
decrease in serum uric acid of approximately 7%. The clinical significance of this weak
uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with
certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded
from clinical studies during the product’s premarket testing. However, the electrocardiograms of
774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate
that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day)
was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a
DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or
unstable angina requiring hospitalization. Exclusions from this trial included, among others,
patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3
months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina,
clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic
dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days
post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this
study on the following week 16 treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF,
MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving
death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment,
sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.
The effects of sertraline in patients with moderate and severe hepatic impairment have not been
studied. The use of sertraline in patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or less frequent dose should
be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy
volunteers to that in patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease.
Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with
renal impairment (see CLINICAL PHARMACOLOGY).
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Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance (See Information for
Patients).
Hyponatremia–Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including ZOLOFT. In many cases, this hyponatremia appears to be the result of the syndrome
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT
should be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Platelet Function– There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking ZOLOFT. While there have been reports of
abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with ZOLOFT and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is
available for ZOLOFT. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents of
the Medication Guide and to obtain answers to any questions they may have. The complete text
of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking ZOLOFT.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Families and
caregivers of patients should be advised to look for the emergence of such symptoms on a day-
to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s
prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of
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the patient’s presenting symptoms. Symptoms such as these may be associated with an increased
risk for suicidal thinking and behavior and indicate a need for very close monitoring and
possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
SNRIs and SSRIs, including ZOLOFT, and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Zoloft can cause mild pupillary dilation, which in
susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing
glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when
diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk
factor for angle closure glaucoma. Patients may wish to be examined to determine whether they
are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they
are susceptible.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to ZOLOFT
they should be careful doing activities when they need to be alert, such as driving a car or
operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant
use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any
OTC product should be initiated cautiously according to the directions of use given for the OTC
product.
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
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Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for persons with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
Laboratory Tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in
patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive
test results may be expected for several days following discontinuation of sertraline therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline
from benzodiazepines.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline
hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other
tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or
placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT
compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the
ZOLOFT group was delayed compared to the placebo group. The clinical significance of this
change is unknown. Accordingly, prothrombin time should be carefully monitored when
ZOLOFT therapy is initiated or stopped.
Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of
cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean
AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs–In a study comparing the disposition of intravenously administered
diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating
dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the
ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a
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20% decrease in the placebo group (p<0.03). The clinical significance of these changes is
unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT
did not significantly alter steady-state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.)
co-administration to steady state was associated with a mean increase in pimozide AUC and
Cmax of about 40%, but was not associated with any changes in EKG. Since the highest
recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the
effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.
While the mechanism of this interaction is unknown, due to the narrow therapeutic index of
pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration
of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of
sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored
following initiation of ZOLOFT therapy with appropriate adjustments to the phenytoin dose,
particularly in patients with multiple underlying medical conditions and/or those receiving
multiple concomitant medications.
The effect of ZOLOFT on valproate levels has not been evaluated in clinical trials. In the
absence of such data, it is recommended that plasma valproate levels be monitored following
initiation of ZOLOFT therapy with appropriate adjustments to the valproate dose.
The risk of using ZOLOFT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant administration of
ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other
drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder,
panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety
disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching,
particularly from long-acting agents. The duration of an appropriate washout period which
should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to
another has not been established.
Monoamine Oxidase Inhibitors – See CONTRAINDICATIONS, WARNINGS, and DOSAGE
AND ADMINISTRATION.
Drugs Metabolized by P450 3A4–In three separate in vivo interaction studies, sertraline was co
administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride
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under steady-state conditions. The results of these studies indicated that sertraline did not
increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate
that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical
significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.)
induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6–Many drugs effective in the treatment of major depressive
disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in
the treatment of major depressive disorder inhibit the biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase
the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The
drugs for which this potential interaction is of greatest concern are those metabolized primarily
by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs
effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics
propafenone and flecainide. The extent to which this interaction is an important clinical problem
depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic
index of the co-administered drug. There is variability among the drugs effective in the treatment
of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact
sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the
class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.
Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require
lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under
PRECAUTIONS).
Serotonergic Drugs – See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND
ADMINISTRATION.
Triptans – There have been rare post marketing reports of serotonin syndrome with use of an
SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including
ZOLOFT, with a triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases (see WARNINGS – Serotonin
Syndrome).
Sumatriptan–There have been rare post marketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor
(SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate
observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder
(TCAs)–The extent to which SSRI–TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
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metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may
need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450
2D6 under PRECAUTIONS).
Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of
ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically
significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous
1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein
binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased
clearance was due to a change in the metabolism of the drug. The clinical significance of this
decrease in tolbutamide clearance is unknown.
Atenolol–ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on
the beta-adrenergic blocking ability of atenolol.
Digoxin–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or
digoxin renal clearance.
Microsomal Enzyme Induction–Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes
minimally as determined by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small change in antipyrine
half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) –
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when ZOLOFT is initiated or
discontinued.
Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of the
combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Alcohol–Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and
Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and
2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a
dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg
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(0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of
either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas.
Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of
unknown significance to humans. There was an increase in follicular adenomas of the thyroid in
female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not
accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in
rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to
placebo controls, this effect was not clearly drug related.
Mutagenesis–Sertraline had no genotoxic effects, with or without metabolic activation, based on
the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for
cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment of Fertility–A decrease in fertility was seen in one of two rat studies at a dose of
80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and
rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were
given sertraline during the period of organogenesis, delayed ossification was observed in fetuses
at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of
gestation and throughout lactation, there was an increase in the number of stillborn pups and in
the number of pups dying during the first 4 days after birth. Pup body weights were also
decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg
(1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg
(0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in
utero exposure to sertraline. The clinical significance of these effects is unknown. There are no
adequate and well-controlled studies in pregnant women. ZOLOFT (sertraline hydrochloride)
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Pregnancy-Nonteratogenic Effects - Neonates exposed to ZOLOFT and other SSRIs or
serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Reported clinical findings
have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,
irritability, and constant crying. These features are consistent with either a direct toxic effect of
SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some
cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin
Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general
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population and is associated with substantial neonatal morbidity and mortality. Several recent
epidemiologic studies suggest a positive statistical association between SSRI use (including
ZOLOFT) in pregnancy and PPHN. Other studies do not show a significant statistical
association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant
women with a history of major depression, who were either on antidepressants or had received
antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.
Women who discontinued antidepressant medication during pregnancy showed a significant
increase in relapse of their major depression compared to those women who remained on
antidepressant medication throughout pregnancy.
When treating a pregnant woman with ZOLOFT, the physician should carefully consider both
the potential risks of taking an SSRI, along with the established benefits of treating depression
with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery–The effect of ZOLOFT on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its
metabolites are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was
demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the
pediatric population other than pediatric patients with OCD have not been established (see BOX
WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled
trials (n=373) in pediatric patients with MDD have been conducted with ZOLOFT, and the data
were not sufficient to support a claim for use in pediatric patients. Anyone considering the use
of ZOLOFT in a child or adolescent must balance the potential risks with the clinical need.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible
dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial
12-week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either
25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in
weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day
based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12
week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally
similar to that observed in adults.
26
Reference ID: 3626722
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of
age with major depressive disorder or OCD and revealed similar drug exposures to those of
adults when plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of
age have received ZOLOFT in clinical trials, both controlled and uncontrolled. The adverse
event profile observed in these patients was generally similar to that observed in adult studies
with ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and
weight loss have been observed in association with the use of ZOLOFT. In a pooled analysis of
two
10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major
depressive disorder (n=373), there was a difference in weight change between sertraline and
placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in
both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.
At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At
baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo.
There was a bigger difference between sertraline and placebo in the proportion of outliers for
clinically important weight loss in children than in adolescents. For children, about 7% had a
weight loss > 7% of body weight compared to none of the placebo patients; for adolescents,
about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients.
A subset of these patients who completed the randomized controlled trials (sertraline n=99,
placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A
mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for
subjects with first exposure to sertraline during the open-label extension study, similar to mean
weight loss observed among sertraline treated subjects during the first eight weeks of the
randomized controlled trials. The subjects continuing in the open label study began gaining
weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed
34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label,
n=68) had weight gain that was similar to that expected using data from age-adjusted peers.
Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with
an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age
of 6 have not been established.
The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and
adolescents with OCD or major depressive disorder have not been systematically assessed. The
prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for
use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration
and from the extrapolation of experience gained with adult patients. In particular, there are no
studies that directly evaluate the effects of long-term sertraline use on the growth, development,
and maturation of children and adolescents. Although there is no affirmative finding to suggest
that sertraline possesses a capacity to adversely affect growth, development or maturation, the
absence of such findings is not compelling evidence of the absence of the potential of sertraline
to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide
Risk).
27
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects 65 years of age, of those, 180 were 75 years of age. No
overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial
subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other
reported experience has not identified differences in safety patterns between the elderly and
younger subjects. As with all medications, greater sensitivity of some older individuals cannot be
ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in
major depressive disorder. No overall differences in the pattern of efficacy were observed in the
geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in
placebo-controlled trials, the overall profile of adverse events was generally similar to that
shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in
Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event (see
PRECAUTIONS, Hyponatremia).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to
ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies,
open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient
studies, fixed-dose and titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced a treatment-emergent adverse event of the type cited on at least one occasion while
receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation. It is important to emphasize
that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
28
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
involving different treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution of drug and
non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-
emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for
ZOLOFT and at least twice that for placebo within at least one of the indications) for the
treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD,
PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major
depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies
received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout
the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing
during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3
enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients
treated with ZOLOFT and with incidence greater than placebo who participated in controlled
clinical trials comparing ZOLOFT with placebo in the treatment of major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3
provides combined data for the pool of studies that are provided separately by indication in
Table 2.
29
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 2
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
"
Percentage of Patients Reporting Event"
"
Major Depressive
Disorder/Other*"
OCD"
Panic Disorder"
PTSD"
Body System/Adverse Event
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
7
<1
17
2
19
1
11
1
Mouth Dry
16
9
14
9
15
10
11
6
Sweating Increased
8
3
6
1
5
1
4
2
Center. & Periph. Nerv. System
Disorders
Somnolence
13
6
15
8
15
9
13
9
Tremor
11
3
8
1
5
1
5
1
Dizziness
12
7
17
9
10
10
8
5
General
Fatigue
11
8
14
10
11
6
10
5
Pain
1
2
3
1
3
3
4
6
Malaise
<1
1
1
1
7
14
10
10
Gastrointestinal Disorders
Abdominal Pain
2
2
5
5
6
7
6
5
Anorexia
3
2
11
2
7
2
8
2
Constipation
8
6
6
4
7
3
3
3
Diarrhea/Loose Stools
18
9
24
10
20
9
24
15
Dyspepsia
6
3
10
4
10
8
6
6
Nausea
26
12
30
11
29
18
21
11
Psychiatric Disorders
Agitation
6
4
6
3
6
2
5
5
Insomnia
16
9
28
12
25
18
20
11
Libido Decreased
1
<1
11
2
7
1
7
2
"
PMDD
Daily Dosing
PMDD
Luteal Phase Dosing(2)
Uqel n" pzlgv{"Fl.qtfgt"
"
Body System/Adverse Event
ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
Autonomic Nervous System
Disorders
Ejaculation Failure(1)
N/A
N/A
N/A
N/A
14
-
Mouth Dry
6
3
10
3
12
4
Sweating Increased
6
<1
3
0
11
2
Center. & Periph. Nerv. System
Disorders
Somnolence
7
<1
2
0
9
6
Tremor
2
0
<1
<1
9
3
Dizziness
6
3
7
5
14
6
General
Fatigue
16
7
10
<1
12
6
Pain
6
<1
3
2
1
3
Malaise
9
5
7
5
8
3
Gastrointestinal Disorders
Abdominal Pain
7
<1
3
3
5
5
Anorexia
3
2
5
0
6
3
Constipation
2
3
1
2
5
3
Diarrhea/Loose Stools
13
3
13
7
21
8
Dyspepsia
7
2
7
3
13
5
Nausea
23
9
13
3
22
8
Psychiatric Disorders
Agitation
2
<1
1
0
4
2
Insomnia
17
11
12
10
25
10
Libido Decreased
11
2
4
2
9
3
30
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive
disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216
ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients
in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
(2)The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing
regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2
should be avoided.
31
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 3
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety Disorder combined
Body System/Adverse Event**
ZOLOFT
(N=2799)"
Placebo
(N=2394)"
"
"
"
Autonomic Nervous System Disorders"
"
"
Ejaculation Failure(1)"
14"
1"
Mouth Dry"
14"
8"
Sweating Increased"
7"
2"
Center. & Periph. Nerv. System Disorders"
"
"
Somnolence"
13"
7"
Dizziness"
12"
7"
Headache"
25"
23"
Paresthesia"
2"
1"
Tremor"
8"
2"
Disorders of Skin and Appendages"
"
"
Rash"
3"
2"
Gastrointestinal Disorders"
"
"
Anorexia"
6"
2"
Constipation"
6"
4"
Diarrhea/Loose Stools"
20"
10"
Dyspepsia"
8"
4"
Nausea"
25"
11"
Vomiting"
4"
2"
General"
"
"
Fatigue"
12"
7"
Psychiatric Disorders"
"
"
Agitation"
5"
3"
Anxiety"
4"
3"
Insomnia"
21"
11"
Libido Decreased"
6"
2"
Nervousness"
5"
4"
Special Senses"
Vision Abnormal"
3"
2
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had
an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
32
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Associated with Discontinuation in Placebo-Controlled Clinical Trials
Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline
hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT
in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder.
TABLE 4
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse
Event"
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
(N=2799)"
Major
Depressive
Disorder/
Other*
(N=861)"
OCD
(N=533)"
Panic
Disorder
(N=430)"
PTSD
(N=374)
PMDD
Daily
Dosing
(N=121)
PMDD
Luteal
Phase
Dosing
(N=136)
Social
Anxiety
Disorder
(N=344)
Abdominal
Pain
–
–
–
–
–
–
–
1%
Agitation"
–"
1%"
–"
2%"
–
–
–
–
Anxiety
–
–
–
–
–
–
–
2%
Diarrhea/
Loose Stools"
2%"
2%"
2%"
1%"
–
2%
–
–
Dizziness"
–"
–"
1%"
–"
–
–
–
–
Dry Mouth
–
1%
–"
–
–
–
–
–
Dyspepsia"
–"
–"
–"
1%"
–
–
–
–
Ejaculation
Failure(1)"
1%"
1%"
1%"
2%"
–
N/A
N/A
2%
Fatigue
–
–
–
–
–
–
–
2%
Headache"
1%"
2%"
–"
–"
1%
–
–
2%
Hot Flushes
–
–
–
–
–
–
1%
–
Insomnia"
2%"
1%"
3%"
2%"
–
–
1%
3%
Nausea"
3%"
4%"
3%"
3%"
2%
2%
1%
2%
Nervousness
–
–
–
–
–
2%
–
–
Palpitation
–
–
–
–
–
–
1%
–
Somnolence"
1%"
1%"
2%"
2%"
–
–
–
–
Tremor
–
2%
–"
–"
–
–
–
–
(1)Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive
disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors
(SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and
severity of untoward experiences involving sexual desire, performance and satisfaction are
33
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual incidence.
Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 5
Adverse Event
ZOLOFT
Placebo
Ejaculation failure*
(primarily delayed ejaculation)
14%
1%
Decreased libido**
6%
1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with
ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies.
However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3,
were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo
rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence,
aggressive reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline
hydrochloride)–Following is a list of treatment-emergent adverse events reported during
premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those
already listed in the previous tables or elsewhere in labeling.
In the tabulations that follow, a World Health Organization dictionary of terminology has been
used to classify reported adverse events. The frequencies presented, therefore, represent the
proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who
experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All
events are included except those already listed in the previous tables or elsewhere in labeling and
those reported in terms so general as to be uninformative and those for which a causal
relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the
events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.
34
Reference ID: 3626722
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major
clinical importance are also described in the PRECAUTIONS section.
Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased
saliva, cold clammy skin, mydriasis; Rare: pallor, angle-closure glaucoma, priapism,
vasodilation.
Body as a Whole–General Disorders–Rare: allergic reaction, allergy.
Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension,
peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal
chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia;
Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin,
erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Endocrine Disorders–Rare: exophthalmos, gynecomastia.
Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries
aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia,
hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum
hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue
ulceration.
General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.
Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.
Liver and Biliary System Disorders–Rare: abnormal hepatic function.
Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia
reaction.
35
Reference ID: 3626722
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability,
apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction,
aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased,
somnambulism, illusion.
Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis,
breast enlargement, atrophic vaginitis, acute female mastitis.
Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea,
stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention,
dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal
pain, strangury.
Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST]
and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with
ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually
occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately
3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid
(approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in patients with major depressive disorder,
OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
Other Events Observed During the Post marketing Evaluation of ZOLOFT–Reports of
adverse events temporally associated with ZOLOFT that have been received since market
introduction, that are not listed above and that may have no causal relationship with the drug,
include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic
neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias,
QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias),
cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming
syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia,
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thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia,
galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin
syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be
fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous
disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority
of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in one or more
patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice,
abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class–ZOLOFT (sertraline hydrochloride) is not a controlled substance.
Physical and Psychological Dependence–In a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans,
ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as
euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical
experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or
barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians
should carefully evaluate patients for history of drug abuse and follow such patients closely,
observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience– Of 1,027 cases of overdose involving sertraline hydrochloride worldwide,
alone or with other drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted
in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue,
insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown
outcome. The most common signs and symptoms associated with non-fatal sertraline
hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation
and tremor.
The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone
and subsequently recovered. However, another patient who took 2.5 grams of sertraline
hydrochloride alone experienced a fatal outcome.
Other important adverse events reported with sertraline hydrochloride overdose (single or
multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,
hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor, syncope and Torsade de Pointes.
Overdose Management–Treatment should consist of those general measures employed in the
management of overdosage with any antidepressant.
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Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug,
forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians’ Desk Reference®
(PDR®).
DOSAGE AND ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder–ZOLOFT treatment should
be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder–ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should
be increased to 50 mg once daily.
While a relationship between dose and effect has not been established for major depressive
disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range
of 50-200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is
recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may
benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination
half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder–ZOLOFT treatment should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the
menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were
dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual
cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a
50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to
150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing
during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with
luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning
of each luteal phase dosing period.
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ZOLOFT should be administered once daily, either in the morning or evening.
Dosage for Pediatric Population (Children and Adolescents)
Obsessive-Compulsive Disorder–ZOLOFT treatment should be initiated with a dose of 25 mg
once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for OCD, patients were
dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of
ZOLOFT for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For
children with OCD, their generally lower body weights compared to adults should be taken into
consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour
elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.
ZOLOFT should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder–It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy beyond response
to the acute episode. Systematic evaluation of ZOLOFT has demonstrated that its antidepressant
efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a
dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder–It is generally agreed that PTSD requires several months or
longer of sustained pharmacological therapy beyond response to initial treatment. Systematic
evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of
up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials
under CLINICAL PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment.
Social Anxiety Disorder–Social anxiety disorder is a chronic condition that may require several
months or longer of sustained pharmacological therapy beyond response to initial treatment.
Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is
maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder–It is generally agreed that OCD and
Panic Disorder require several months or longer of sustained pharmacological therapy beyond
response to initial treatment. Systematic evaluation of continuing ZOLOFT for periods of up to
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28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day
has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment.
Premenstrual Dysphoric Disorder–The effectiveness of ZOLOFT in long-term use, that is, for
more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.
However, as women commonly report that symptoms worsen with age until relieved by the onset
of menopause, it is reasonable to consider continuation of a responding patient. Dosage
adjustments, which may include changes between dosage regimens (e.g., daily throughout the
menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to
maintain the patient on the lowest effective dosage and patients should be periodically reassessed
to determine the need for continued treatment.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to
Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an
MAOI intended to treat psychiatric disorders and initiation of therapy with ZOLOFT.
Conversely, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI
intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of ZOLOFT With Other MAOIs Such as Linezolid or Methylene Blue: Do not start
ZOLOFT in a patient who is being treated with linezolid or intravenous methylene blue because
there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of
a psychiatric condition, other interventions, including hospitalization, should be considered (see
CONTRAINDICATIONS).
In some cases, a patient already receiving ZOLOFT therapy may require urgent treatment with
linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous
methylene blue treatment are not available and the potential benefits of linezolid or intravenous
methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular
patient, ZOLOFT should be stopped promptly, and linezolid or intravenous methylene blue can
be administered. The patient should be monitored for symptoms of serotonin syndrome for 2
weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with ZOLOFT may be resumed 24 hours after the last dose of linezolid or
intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by
local injection) or in intravenous doses much lower than 1 mg/kg with ZOLOFT is unclear. The
clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin
syndrome with such use (see WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients–The use of sertraline in patients with liver disease
should be approached with caution. The effects of sertraline in patients with moderate and severe
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hepatic impairment have not been studied. If sertraline is administered to patients with liver
impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
Treatment of Pregnant Women During the Third Trimester–Neonates exposed to ZOLOFT
and other SSRIs or SNRIs, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When
treating pregnant women with ZOLOFT during the third trimester, the physician should carefully
consider the potential risks and benefits of treatment.
Discontinuation of Treatment with ZOLOFT
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been
reported (see PRECAUTIONS). Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active
ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before
taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze
may appear after mixing; this is normal. Note that caution should be exercised for patients with
latex sensitivity, as the dropper dispenser contains dry natural rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.
HOW SUPPLIED
ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline
hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 25 mg.
NDC 0049-4960-30
Bottles of 30
NDC 0049-4960-50
Bottles of 50
ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and
on the other side scored and engraved with 50 mg.
NDC 0049-4900-30
Bottles of 30
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NDC 0049-4900-66
Bottles of 100
NDC 0049-4900-73
Bottles of 500
NDC 0049-4900-94
Bottles of 5000
NDC 0049-4900-41
Unit Dose Packages of 100
ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT
and on the other side scored and engraved with 100 mg.
NDC 0049-4910-30
Bottles of 30
NDC 0049-4910-66
Bottles of 100
NDC 0049-4910-73
Bottles of 500
NDC 0049-4910-94
Bottles of 5000
NDC 0049-4910-41
Unit Dose Packages of 100
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F)[see USP Controlled Room
Temperature].
ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.
NDC 0049-4940-23
Bottles of 60 mL
Store at 25C (77F); excursions permitted to 15 - 30C (59° - 86°F) [see USP Controlled
Room Temperature].
Rx only company logo
LAB-0218-33.0
Revised August 2014
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Medication Guide
ZOLOFT (ZOH-loft)
(sertraline hydrochloride)
(Tablets and Oral Concentrate (solution))
Read the Medication Guide that comes with ZOLOFT before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there
is something you do not understand or want to learn more about.
What is the most important information I
should know about ZOLOFT?
ZOLOFT and other antidepressant medicines
may cause serious side effects, including:
1. Suicidal thoughts or actions:
ZOLOFT and other antidepressant
medicines may increase suicidal thoughts
or actions in some children, teenagers, or
young adults within the first few months of
treatment or when the dose is changed.
Depression or other serious mental illnesses
are the most important causes of suicidal
thoughts or actions.
Watch for these changes and call your
healthcare provider right away if you notice:
New or sudden changes in mood,
behavior, actions, thoughts, or feelings,
especially if severe.
Pay particular attention to such changes
when ZOLOFT is started or when the
dose is changed.
Keep all follow-up visits with your
healthcare provider and call between visits if
you are worried about symptoms.
Call your healthcare provider right away
if you have any of the following
symptoms, or call 911 if an emergency,
especially if they are new, worse, or worry
you:
attempts to commit suicide
acting on dangerous impulses
acting aggressive or violent
thoughts about suicide or dying
new or worse depression
new or worse anxiety or panic
attacks
feeling agitated, restless, angry or
irritable
trouble sleeping
an increase in activity or talking
more than what is normal for you
other unusual changes in behavior
or mood
Call your healthcare provider right away if
you have any of the following symptoms, or
call 911 if an emergency. ZOLOFT may be
associated with these serious side effects:
2. Serotonin Syndrome
This condition can be life-threatening and
may include:
agitation, hallucinations, coma or other
changes in mental status
coordination problems or muscle
twitching (overactive reflexes)
racing heartbeat, high or low blood
pressure
sweating or fever
nausea, vomiting, or diarrhea
muscle rigidity
3. Severe allergic reactions:
trouble breathing
swelling of the face, tongue, eyes or
mouth
rash, itchy welts (hives) or blisters,
alone or with fever or joint pain
4. Abnormal bleeding: ZOLOFT and other
antidepressant medicines may increase your
risk of bleeding or bruising, especially if
you take the blood thinner warfarin
(Coumadin®, Jantoven®), a non-steroidal
anti-inflammatory drug (NSAIDs, like
ibuprofen or naproxen), or aspirin.
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5. Seizures or convulsions
6. Manic episodes:
greatly increased energy
severe trouble sleeping
racing thoughts
reckless behavior
unusually grand ideas
excessive happiness or irritability
talking more or faster than usual
7. Changes in appetite or weight. Children
and adolescents should have height and
weight monitored during treatment.
8. Low salt (sodium) levels in the blood.
Elderly people may be at greater risk for
this. Symptoms may include:
headache
weakness or feeling unsteady
confusion, problems concentrating or
thinking or memory problems
9. Visual problems
eye pain
changes in vision
swelling or redness in or around the eye
Only some people are at risk for these
problems. You may want to undergo an eye
examination to see if you are at risk and
receive preventative treatment if you are.
Do not stop ZOLOFT without first talking to
your healthcare provider. Stopping ZOLOFT
too quickly may cause serious symptoms
including:
anxiety, irritability, high or low mood,
feeling restless or changes in sleep habits
headache, sweating, nausea, dizziness
electric shock-like sensations, shaking,
confusion
What is ZOLOFT?
ZOLOFT is a prescription medicine used to treat
depression. It is important to talk with your
healthcare provider about the risks of treating
depression and also the risks of not treating it.
You should discuss all treatment choices with
your healthcare provider. ZOLOFT is also used
to treat:
Major Depressive Disorder (MDD)
Obsessive Compulsive Disorder (OCD)
Panic Disorder
Posttraumatic Stress Disorder (PTSD)
Social Anxiety Disorder
Premenstrual Dysphoric Disorder (PMDD)
Talk to your healthcare provider if you do not
think that your condition is getting better with
ZOLOFT treatment.
Who should not take ZOLOFT?
Do not take ZOLOFT if you:
are allergic to sertraline or any of the
ingredients in ZOLOFT. See the end of this
Medication Guide for a complete list of
ingredients in ZOLOFT.
take the antipsychotic medicine pimozide
(Orap®) because this can cause serious
heart problems.
take Antabuse® (disulfiram) (if you are
taking the liquid form of ZOLOFT) due to
the alcohol content.
take a monoamine oxidase inhibitor
(MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an
MAOI, including the antibiotic linezolid.
Do not take an MAOI within 2 weeks of
stopping ZOLOFT unless directed to do so
by your physician.
Do not start ZOLOFT if you stopped taking
an MAOI in the last 2 weeks unless directed
to do so by your physician.
People who take ZOLOFT close in time to
an MAOI may have serious or even life-
threatening side effects. Get medical help
right away if you have any of these
symptoms:
high fever
uncontrolled muscle spasms
stiff muscles
rapid changes in heart rate or blood
pressure
confusion
loss of consciousness (pass out)
What should I tell my healthcare provider
before taking ZOLOFT? Ask if you are not
sure.
Before starting ZOLOFT, tell your healthcare
provider if you:
Are taking certain drugs such as:
Medicines used to treat migraine
headaches such as:
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o triptans
the best way to feed your baby while taking
Medicines used to treat mood, anxiety,
ZOLOFT.
psychotic or thought disorders, such as:
o tricyclic antidepressants
o lithium
o diazepam
o SSRIs
o SNRIs
o antipsychotic drugs
o valproate
Medicines used to treat seizures such as:
o phenytoin
Medicines used to treat pain such as:
o tramadol
Medicines used to thin your blood such
as:
o warfarin
Medicines used to control your
heartbeat such as :
o propafenone
o flecainide
o digitoxin
Medicines used to treat type II diabetes
such as:
o tolbutamide
Cimetidine used to treat heartburn
Over-the-counter medicines or
supplements such as:
o Aspirin or other NSAIDs
o tryptophan
o St. John’s Wort
have liver problems
have kidney problems.
have heart problems
have or had seizures or convulsions
have bipolar disorder or mania
have low sodium levels in your blood
have a history of a stroke
have high blood pressure
have or had bleeding problems
are pregnant or plan to become pregnant. It
is not known if ZOLOFT will harm your
unborn baby. Talk to your healthcare
provider about the benefits and risks of
treating depression during pregnancy.
are breast-feeding or plan to breast-feed.
Some ZOLOFT may pass into your breast
milk. Talk to your healthcare provider about
Tell your healthcare provider about all the
medicines that you take, including prescription
and non-prescription medicines, vitamins, and
herbal supplements. ZOLOFT and some
medicines may interact with each other, may not
work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell
you if it is safe to take ZOLOFT with your other
medicines. Do not start or stop any medicine
while taking ZOLOFT without talking to your
healthcare provider first.
If you take ZOLOFT, you should not take any
other medicines that contain sertraline (sertraline
HCl, sertraline hydrochloride, etc.).
How should I take ZOLOFT?
Take ZOLOFT exactly as prescribed. Your
healthcare provider may need to change the
dose of ZOLOFT until it is the right dose for
you.
ZOLOFT Tablets may be taken with or
without food.
ZOLOFT Oral Concentrate must be diluted
before use:
o Follow the instructions carefully
o When diluting ZOLOFT Oral
Concentrate, use ONLY water,
ginger ale, lemon/lime soda,
lemonade, or orange juice.
o If you are sensitive to latex, be
careful when using the dropper to
dispense the Oral Concentrate.
If you miss a dose of ZOLOFT, take the
missed dose as soon as you remember. If it
is almost time for the next dose, skip the
missed dose and take your next dose at the
regular time. Do not take two doses of
ZOLOFT at the same time.
If you take too much ZOLOFT, call your
healthcare provider or poison control center
right away, or get emergency treatment.
What should I avoid while taking ZOLOFT?
ZOLOFT can cause sleepiness or may affect
your ability to make decisions, think clearly, or
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react quickly. You should not drive, operate
heavy machinery, or do other dangerous
activities until you know how ZOLOFT affects
you. Do not drink alcohol while using ZOLOFT.
What are the possible side effects of
ZOLOFT?
ZOLOFT may cause serious side effects,
including:
See “What is the most important
information I should know about
ZOLOFT?”
Feeling anxious or trouble sleeping
Common possible side effects in people who
take ZOLOFT include:
nausea, loss of appetite, diarrhea or
indigestion
change in sleep habits including
increased sleepiness or insomnia
increased sweating
sexual problems including decreased
libido and ejaculation failure
tremor or shaking
feeling tired or fatigued
agitation
Other side effects in children and adolescents
include:
abnormal increase in muscle movement
or agitation
nose bleed
urinating more often
urinary incontinence
aggressive reaction
heavy menstrual periods
possible slowed growth rate and weight
change. Your child’s height and weight
should be monitored during treatment
with ZOLOFT.
Tell your healthcare provider if you have any
side effect that bothers you or that does not go
away. These are not all the possible side effects
of ZOLOFT. For more information, ask your
healthcare provider or pharmacist.
CALL YOUR DOCTOR FOR MEDICAL
ADVICE ABOUT SIDE EFFECTS. YOU
MAY REPORT SIDE EFFECTS TO THE
FDA AT 1-800-FDA-1088.
How should I store ZOLOFT?
Store ZOLOFT at room temperature,
between 59°F and 86°F (15°C to 30°C).
Keep ZOLOFT bottle closed tightly.
Keep ZOLOFT and all medicines out of the
reach of children.
General information about ZOLOFT
Medicines are sometimes prescribed for
purposes other than those listed in a Medication
Guide. Do not use ZOLOFT for a condition for
which it was not prescribed. Do not give
ZOLOFT to other people, even if they have the
same condition. It may harm them.
This Medication Guide summarizes the most
important information about ZOLOFT. If you
would like more information, talk with your
healthcare provider. You may ask your
healthcare provider or pharmacist for
information about ZOLOFT that is written for
healthcare professionals.
For more information about ZOLOFT call
1-800-438-1985 or go to www.pfizer.com
What are the ingredients in ZOLOFT?
Active ingredient: sertraline hydrochloride
Inactive ingredients
Tablets: dibasic calcium phosphate
dihydrate, D&C Yellow #10 aluminum lake
(in 25 mg tablet), FD&C Blue #1 aluminum
lake (in 25 mg tablet), FD&C Red #40
aluminum lake (in 25 mg tablet), FD&C
Blue #2 aluminum lake (in 50 mg tablet),
hydroxypropyl cellulose, hypromellose,
magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, synthetic
yellow iron oxide (in 100 mg tablet), and
titanium dioxide
Oral concentration: glycerin, alcohol
(12%), menthol, butylated hydroxytoluene
(BHT)
This Medication Guide has been approved by
the U.S. Food and Drug Administration
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company logo
LAB-0540-4.0
Revised May 2014
Reference ID: 3626722
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:05.347929
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019839s084,020990s043lbl.pdf', 'application_number': 19839, 'submission_type': 'SUPPL ', 'submission_number': 84}
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11,767
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____________________________________________________________________________________________________________
NDA 19-845/S-021
Page 3
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed
to use Betoptic S® safely and effectively. See full
prescribing information for Betoptic S®.
Betoptic S® (betaxolol hydrochloride ophthalmic
suspension) 0.25% as base, Sterile topical ophthalmic
drops
Initial U.S. Approval: 1985
------------------RECENT MAJOR CHANGES-----------------
Use in Specific Populations, Pediatric Use (8.4)
6/2007
------------------INDICATIONS AND USAGE------------------
BETOPTIC S® is a beta-adrenergic receptor inhibitor
indicated for the treatment of elevated intraocular pressure in
patients with chronic open-angle glaucoma or ocular
hypertension (1).
--------------DOSAGE AND ADMINISTRATION-------------
•
Instill one drop in the affected eye(s) twice daily (2)
-------------DOSAGE FORMS AND STRENGTHS------------
•
Bottles filled with 2.5, 5, 10, and 15 mL of 0.25% sterile
ophthalmic suspension (3)
---------------------CONTRAINDICATIONS---------------------
•
Hypersensitivity to any component of this product (4)
•
Sinus bradycardia, second or third degree atrioventricular
block, overt cardiac failure, and cardiogenic shock (4)
---------------WARNINGS AND PRECAUTIONS-------------
•
Same adverse reactions found with systemic
administration of beta-adrenergic receptor inhibitors may
occur with topical ophthalmic administration (5.1).
•
Beta-adrenergic receptor inhibitors may mask the signs
and symptoms of acute hypoglycemia and should be
administered with caution in diabetic patients subject to
hypoglycemia (5.3).
•
Beta-adrenergic receptor inhibitors may mask certain
clinical signs (e.g. tachycardia) or hyperthyroidism (5.4).
---------------------ADVERSE REACTIONS---------------------
The most frequent adverse reaction is transient ocular
discomfort (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact
Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------DRUG INTERACTIONS---------------------
•
Oral beta-adrenergic receptor inhibitors may have
additive effects (7.1)
•
Catecholamine-depleting drugs may have additive effects
(7.2)
•
Concomitant adrenergic psychotropic drugs may have
additive effects (7.3)
See 17 for PATIENT COUNSELING INFORMATION
and FDA-approved patient labeling.
Revised: XX/2007
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
General
5.2
Cardiac Failure
5.3
Diabetes Mellitus
5.4
Thyrotoxicosis
5.5
Muscle Weakness
5.6
Surgical Anesthesia
5.7
Bronchospasm and Obstructive Pulmonary
Disease
5.8
Atopy/Anaphylaxis
5.9
Angle-Closure Glaucoma
5.10 Cerebrovascular Insufficiency
5.11 Bacterial Keratitis
5.12 Choroidal Detachment
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
6.2
Additional Potential Adverse Reactions
Associated with Betaxolol
7
DRUG INTERACTIONS
7.1
Oral Beta-Adrenergic Receptor Inhibitors
7.2
Catecholamine-Depleting Drugs
7.3
Concomitant Adrenergic Psychotropic Drugs
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
BETOPTIC S® Ophthalmic Suspension 0.25% is
indicated for the treatment of elevated intraocular
pressure in patients with chronic open-angle glaucoma or
ocular hypertension.
2
DOSAGE AND ADMINISTRATION
Instill one drop of BETOPTIC S® Ophthalmic
Suspension 0.25% in the affected eye twice daily. It may
be used alone or in combination with other intraocular
pressure lowering medications.
3
DOSAGE FORMS AND STRENGTHS
Bottle filled with 2.5, 5, 10, and 15 mL of 0.25%
sterile ophthalmic suspension
4
CONTRAINDICATIONS
BETOPTIC S® Suspension is contraindicated in
patients with:
• sinus bradycardia
• greater than a first degree atrioventricular block
• cardiogenic shock
• patients with overt cardiac failure
• hypersensitivity to any component of this
product.
5
WARNINGS AND PRECAUTIONS
5.1
General
As with many topically applied ophthalmic drugs,
this drug is absorbed systemically. The same adverse
reactions found with systemic administration of beta-
adrenergic receptor inhibitors may occur with topical
administration. For example, severe respiratory
reactions and cardiac reactions, including death due to
bronchospasm in patients with asthma, and death due to
cardiac failure, have been reported with topical
application of beta-adrenergic receptor inhibitors.
5.2
Cardiac Failure
BETOPTIC S® Suspension has been shown to
have a minor effect on heart rate and blood pressure in
clinical studies. Caution should be used in treating
patients with a history of cardiac failure or heart block.
Treatment with BETOPTIC S® should be discontinued
at the first signs of cardiac failure.
5.3
Diabetes Mellitus
Beta-adrenergic receptor inhibitors should be
administered with caution in patients subject to
hypoglycemia or to diabetic patients (especially those
with labile diabetes) who are receiving insulin or oral
hypoglycemic agents. Beta-adrenergic receptor
inhibitors may mask the signs and symptoms of acute
hypoglycemia.
5.4
Thyrotoxicosis
Beta-adrenergic receptor inhibitors may mask
certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing
thyrotoxicosis should be managed carefully to avoid
abrupt withdrawal of beta-adrenergic receptor inhibitors,
which might precipitate a thyroid storm.
5.5
Muscle Weakness
Beta-adrenergic receptor inhibitors have been
reported to potentiate muscle weakness consistent with
certain myasthenic symptoms (e.g., diplopia, ptosis and
generalized weakness).
5.6
Surgical Anesthesia
The necessity or desirability of withdrawal of
beta-adrenergic receptor inhibitors prior to major surgery
is controversial. Beta-adrenergic receptor inhibitors
impair the ability of the heart to respond to beta-
adrenergically mediated reflex stimuli. This may
augment the risk of general anesthesia in surgical
procedures. Some patients receiving beta-adrenergic
receptor inhibitors have experienced protracted, severe
hypotension during anesthesia. Difficulty in restarting
and maintaining the heartbeat has also been reported. In
patients undergoing elective surgery, consider gradual
withdrawal of beta-adrenergic receptor inhibitors. If
necessary during surgery, the effects of beta-adrenergic
receptor inhibitors may be reversed by sufficient doses of
adrenergic agonists.
5.7
Bronchospasm and Obstructive
Pulmonary Disease
Caution should be exercised in the treatment of
glaucoma patients with excessive restriction of
pulmonary function. There have been reports of
asthmatic attacks and pulmonary distress during
betaxolol treatment. Although re-challenges of some
such patients with ophthalmic betaxolol has not
adversely affected pulmonary function test results, the
possibility of adverse pulmonary effects in patients
sensitive to beta-adrenergic receptor inhibitors cannot be
ruled out.
5.8
Atopy/Anaphylaxis
While taking beta receptor inhibitors, patients
with a history of atopy or a history of severe
anaphylactic reaction to a variety of allergens may be
more reactive to repeated accidental, diagnostic, or
therapeutic challenge with such allergens. Such patients
may be unresponsive to the usual doses of epinephrine
used to treat anaphylactic reactions.
5.9
Angle-Closure Glaucoma
In patients with angle-closure glaucoma, the
immediate treatment objective is to reopen the angle.
This may require constricting the pupil. Betaxolol has
little or no effect on the pupil and should not be used
alone in the treatment of angle-closure glaucoma.
5.10 Cerebrovascular Insufficiency
Because of potential effects of beta-adrenergic
receptor inhibitors on blood pressure and pulse, these
inhibitors should be used with caution in patients with
cerebrovascular insufficiency. If signs or symptoms
suggesting reduced cerebral blood flow develop
following initiation of therapy with BETOPTIC S®,
alternative therapy should be considered.
5.11 Bacterial Keratitis
Bacterial keratitis may occur with use of multiple
dose containers of topical ophthalmic products when
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-021
Page 2
these containers are inadvertently contaminated by
patients who, in most cases, had a concurrent corneal
disease or a disruption of the ocular epithelial surface.
Instruct patients on appropriate instillation techniques.
[see Patient Counseling Information (17)].
5.12 Choroidal Detachment
Choroidal detachment after filtration procedures
has been reported with the administration of aqueous
suppressant therapy.
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
In clinical trials, the most frequent adverse
reaction associated with the use of BETOPTIC S®
Ophthalmic Suspension 0.25% has been transient ocular
discomfort. The following other adverse reactions have
been reported in small numbers of patients:
Ocular: blurred vision, corneal punctate keratitis,
foreign body sensation, photophobia, tearing, itching,
dryness of eyes, erythema, inflammation, discharge,
ocular pain, decreased visual acuity and crusty lashes.
Systemic adverse reactions include:
Cardiovascular: Bradycardia, heart block and congestive
failure.
Pulmonary: Pulmonary distress characterized by
dyspnea, bronchospasm, thickened bronchial secretions,
asthma and respiratory failure.
Central Nervous System: Insomnia, dizziness,
vertigo, headaches, depression, lethargy, and increase in
signs and symptoms of myasthenia gravis.
Other: Hives, toxic epidermal necrolysis, hair
loss, and glossitis. Perversions of taste and smell have
been reported.
In a 3-month, double-masked, active-controlled,
multicenter study in pediatric patients, the adverse
reaction profile of BETOPTIC S® Ophthalmic
Suspension 0.25% was comparable to that seen in adult
patients.
6.2
Additional Potential Adverse Reactions
Associated with Betaxolol
Additional medical events reported with other
formulations of betaxolol include allergic reactions,
decreased corneal sensitivity, corneal punctate staining
which may appear in dendritic formations, edema and
anisocoria.
7
DRUG INTERACTIONS
7.1
Oral Beta-Adrenergic Receptor
Inhibitors
Patients who are receiving a beta-adrenergic
receptor inhibitor orally and BETOPTIC S® Ophthalmic
Suspension 0.25% should be observed for a potential
additive effect either on the intraocular pressure or on the
known systemic effects of beta blockade.
7.2
Catecholamine-Depleting Drugs
Close observation of the patient is recommended
when a beta-adrenergic receptor inhibitor is administered
to patients receiving catecholamine-depleting drugs such
as reserpine, because of possible additive effects and the
production of hypotension and/or bradycardia which may
result in vertigo, syncope, or postural hypotension.
7.3
Concomitant Adrenergic Psychotropic
Drugs
Betaxolol is an adrenergic receptor inhibitor;
therefore, caution should be exercised in patients using
concomitant adrenergic psychotropic drugs.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic effects
Pregnancy Category C: Reproduction, teratology,
and peri- and postnatal studies have been conducted with
orally administered betaxolol HCl in rats and rabbits.
There was evidence of drug related postimplantation loss
in rabbits and rats at dose levels above 12 mg/kg and 128
mg/kg, respectively. Betaxolol HCl was not shown to be
teratogenic, however, and there were no other adverse
effects on reproduction at subtoxic dose levels. There
are no adequate and well-controlled studies in pregnant
women.
BETOPTIC S® Ophthalmic Suspension 0.25%
should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
8.3
Nursing Mothers
It is not known whether betaxolol HCl is excreted
in human milk. Because many drugs are excreted in
human milk, caution should be exercised when
BETOPTIC S® Ophthalmic Suspension 0.25% is
administered to nursing women.
8.4
Pediatric Use
Safety and IOP-lowering effect of
BETOPTIC S® Ophthalmic Suspension 0.25% has been
demonstrated in pediatric patients in a 3-month,
multicenter, double-masked, active-controlled trial.
8.5
Geriatric Use
No overall differences in safety or effectiveness
have been observed between elderly and younger
patients.
10
OVERDOSAGE
No information is available on overdosage of
humans. The oral LD50 of the drug ranged from 350-920
mg/kg in mice and 860-1050 mg/kg in rats. The
symptoms which might be expected with an overdose of
a systemically administered beta-1-adrenergic receptor
inhibitor are bradycardia, hypotension and acute cardiac
failure.
A topical overdose of BETOPTIC S® Ophthalmic
Suspension 0.25% may be flushed from the eye(s) with
warm tap water.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-021
Page 3
11
DESCRIPTION
BETOPTIC S® Ophthalmic Suspension 0.25%
contains betaxolol hydrochloride, a cardioselective beta-
adrenergic receptor inhibitor, in a sterile resin suspension
formulation. Betaxolol hydrochloride is a white,
crystalline powder, with a molecular weight of 343.89.
The chemical structure is presented below. Chemical Structure
Empirical Formula:
C18H29NO3•HCl
Chemical Name:
(±)-1-[p-[2-(cyclopropylmethoxy)ethyl]phenoxy]
3-(isopropylamino)-2-propanol hydrochloride.
Each mL of BETOPTIC S® Ophthalmic
Suspension 0.25% contains: Active: betaxolol HCl 2.8
mg equivalent to 2.5 mg of betaxolol base.
Preservative: benzalkonium chloride 0.01%.
Inactive(s): Mannitol, Poly(Styrene-Divinyl Benzene)
sulfonic acid, Carbomer 934P, edetate disodium,
hydrochloric acid or sodium hydroxide (to adjust pH)
and purified water.
BETOPTIC S® Ophthalmic Suspension 0.25%
has a pH of approximately 7.6 and an osmolality of
approximately 290 mOsmol/kg.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Betaxolol HCl, a cardioselective (beta-1
adrenergic) receptor inhibitor, does not have significant
membrane-stabilizing (local anesthetic) activity and is
devoid of intrinsic sympathomimetic action. Orally
administered beta-adrenergic receptor inhibitors reduce
cardiac output in healthy subjects and patients with heart
disease. In patients with severe impairment of
myocardial function, beta-adrenergic receptor
antagonists may inhibit the sympathetic stimulatory
effect necessary to maintain adequate cardiac function.
When instilled in the eye, BETOPTIC S®
Ophthalmic Suspension 0.25% has the action of reducing
elevated intraocular pressure, whether or not
accompanied by glaucoma. Ophthalmic betaxolol has
minimal effect on pulmonary and cardiovascular
parameters.
Elevated IOP presents a major risk factor in
glaucomatous field loss. The higher the level of IOP, the
greater the likelihood of optic nerve damage and visual
field loss. Betaxolol has the action of reducing elevated
as well as normal intraocular pressure and the
mechanism of ocular hypotensive action appears to be a
reduction of aqueous production as demonstrated by
tonography and aqueous fluorophotometry.
12.2 Pharmacodynamics
The onset of action with betaxolol can generally
be noted within 30 minutes and the maximum effect can
usually be detected 2 hours after topical administration.
A single dose provides a 12-hour reduction in intraocular
pressure. In some patients, the intraocular pressure
lowering responses to BETOPTIC S® may require a few
weeks to stabilize. As with any new medication, careful
monitoring of patients is advised.
Ophthalmic betaxolol solution at 1% (one drop in
each eye) was compared to placebo in a crossover study
challenging nine patients with reactive airway disease.
Betaxolol HCl had no significant effect on pulmonary
function as measured by FEV1, Forced Vital Capacity
(FVC), FEV1/FVC and was not significantly different
from placebo. The action of isoproterenol, a beta
stimulant, administered at the end of the study was not
inhibited by ophthalmic betaxolol.
No evidence of cardiovascular beta adrenergic-
blockade during exercise was observed with betaxolol in
a double-masked, crossover study in 24 normal subjects
comparing ophthalmic betaxolol and placebo for effects
on blood pressure and heart rate.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis,
Impairment of Fertility
Lifetime studies with betaxolol HCl have been
completed in mice at oral doses of 6, 20 or 60 mg/kg/day
and in rats at 3, 12 or 48 mg/kg/day; betaxolol HCl
demonstrated no carcinogenic effect. Higher dose levels
were not tested.
In a variety of in vitro and in vivo bacterial and
mammalian cell assays, betaxolol HCl was
nonmutagenic.
14
CLINICAL STUDIES
In controlled, double-masked studies, the
magnitude and duration of the ocular hypotensive effect
of BETOPTIC S® Ophthalmic Suspension 0.25% and
BETOPTIC® Ophthalmic Solution 0.5% were clinically
equivalent. BETOPTIC S® Suspension was
significantly more comfortable than BETOPTIC®
Solution.
16
HOW SUPPLIED/STORAGE AND
HANDLING
BETOPTIC S® Ophthalmic Suspension 0.25% is
supplied as follows: 2.5, 5, 10 and 15 mL in plastic
ophthalmic DROP-TAINER® dispensers. Tamper
evidence is provided with a shrink band around the
closure and neck area of the DROP-TAINER package.
2.5 mL: NDC 0065-0246-20
5 mL:
NDC 0065-0246-05
10 mL: NDC 0065-0246-10
15 mL: NDC 0065-0246-15
Storage and Handling
Store upright at 2° - 25°C (36° - 77°F). Shake
well before using.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-845/S-021
Page 4
17
PATIENT COUNSELING INFORMATION How to Use the DROP-TAINER Bottle Image
The DROP-TAINER® bottle is designed to assure the
delivery of a precise dose of medication. Before using
your DROP-TAINER® bottle, read the complete
instructions carefully. How to use drop bottle Illustrations
1.
If you use other topically applied ophthalmic
medications, they should be administered at least
10 minutes before BETOPTIC S®.
2.
Wash hands before each use.
3.
Before using the medication for the first time, be
sure the Safety Seal on the bottle is unbroken.
4.
Tear off the Safety Seal to break the seal.
5.
Before each use, shake well and remove the screw
cap.
6.
Invert the bottle and hold the bottle between your
thumb and middle finger, with the tips of the
Putting drops in eyes Illustration
7.
Tilt your head back and position the bottle above
the affected eye. DO NOT TOUCH THE EYE
WITH THE TIP OF THE DROPPER.
8.
With the opposite hand, place a finger under the
eye. Gently pull down until a “V” pocket is made
between your eye and lower lid.
9.
With the hand holding the bottle, place your index
finger on the bottom of the bottle. Push the
bottom of the bottle to dispense one drop of
medication. DO NOT SQUEEZE THE SIDES
OF THE BOTTLE.
10.
Repeat 6, 7, 8, and 9 with other eye if instructed to
do so.
11.
Replace screw cap by turning until firmly
touching the bottle.
Patients should be instructed to avoid allowing the
tip of the dispensing container to contact the eye(s) or
surrounding structures. Patients should also be
instructed that ocular solutions, if handled improperly,
could become contaminated by common bacteria known
to cause ocular infections. Serious damage to the eye(s)
and subsequent loss of vision may result from using
contaminated solutions.
Patients should be advised that if they have ocular
surgery or develop an intercurrent ocular condition (e.g.,
trauma or infection), they should immediately seek their
physician’s advice concerning the continued use of the
present multidose container.
Patients requiring concomitant topical ophthalmic
medications should be instructed to administer these at
least 10 minutes before instilling BETOPTIC S®
Suspension.
U.S. Patents No. 4,911,920
© 2003, 2007 Alcon, Inc.
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:46:05.355771
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019845s021lbl.pdf', 'application_number': 19845, 'submission_type': 'SUPPL ', 'submission_number': 21}
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11,769
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
08724752, R.6
4/04
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal
volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively;
the concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes
every 12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of
400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral
dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into
cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum
concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in
serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin
to serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200
µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing.
Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after
dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin
in patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-
dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-
hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less
than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5
years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5
µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within
the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children
is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately
60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin
and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin,
probenecid, and piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
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package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms
have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
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Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in situations
where high dosage of drug can be used. This category also provides a buffer zone, which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant”
indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood
reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
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reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test
with a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate
(I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than
“Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should
be submitted to a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
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mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or
Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for
the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae
subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa,
Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably
likely to predict clinical benefit and provide the basis for this indication.4 (See also,
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate
and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO I.V. may be initiated before results of these tests are known; once results become
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available, appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to
ciprofloxacin or any member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature
dogs. Histopathological examination of the weight-bearing joints of these dogs revealed
permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of
cartilage of weight-bearing joints and other signs of arthropathy in immature animals of
various species. (See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
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ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous
antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin
cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-
threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should
be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone.
In moderate to severe cases, consideration should be given to management with fluids and
electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective
against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may
be increased in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin
should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients
should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has
been excluded. Tendon rupture can occur during or after therapy with quinolones, including
ciprofloxacin.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
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the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is
30 minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of
the quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
•that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses
or not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not
be treatable by CIPRO I.V. or other antibacterial drugs in the future.
•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, they should discontinue treatment and contact their physicians.
•to discontinue treatment; rest and refrain from exercise; and inform their physician if they
experience pain, inflammation, or rupture of a tendon.
•that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
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•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18
years of age). Parents should inform their child’s physician if the child has a history of
joint-related problems before taking this drug. Parents of pediatric patients should also
notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and
ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some
patients, resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the
level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
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Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
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For current labeling information, please visit https://www.fda.gov/drugsatfda
studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate
the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg
(0.6 and 0.3 times the maximum daily human dose based upon body surface area,
respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In
rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times
the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal
toxicity resulting in maternal weight loss and an increased incidence of abortion, but no
teratogenicity was observed at either dose level. After intravenous administration of doses up
to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon
mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was
observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed
by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants
nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-
exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is
not a drug of first choice in the pediatric population due to an increased incidence of adverse
events compared to the controls, including those related to joints and/or surrounding tissues.
The rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events
regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10
mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to
complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V.
50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients
less than 5 years of age were not studied. Safety monitoring in the study included periodic
range of motion examinations and gait assessments by treatment-blinded examiners. Patients
were followed for an average of 23 days after completing treatment (range 0-93 days). This
study was not designed to determine long term effects and the safety of repeated exposure to
ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an
MRI showed knee effusion without other abnormalities eight months after treatment.
However, the relationship of this event to the patient’s course of ciprofloxacin can not be
definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the
kidney, and the risk of adverse reactions may be greater in patients with impaired renal
function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal
function by virtue of their advanced age, care should be taken in dose selection for elderly
patients, and renal function monitoring may be useful in these patients. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events
reported were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an
adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
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system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or
moderate in severity, abated soon after the drug was discontinued, and required no treatment.
Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These
may appear as local skin reactions which resolve rapidly upon completion of the infusion.
Subsequent intravenous administration is not contraindicated unless the reactions recur or
worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac
murmur, hypertension, hypotension, angina pectoris, atrial flutter, ventricular ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis,
depression, dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia,
confusion, hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia,
nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal
convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC:
agranulocytosis,
prolongation
of
prothrombin
time,
lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest
pain, achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions,
erythema
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis,
angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever,
chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration,
hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia, erythema, swelling,
photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators
to be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
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In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally,
was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI)
or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The
trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa,
and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11
days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety within 6 weeks of therapy and through one year of
follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline
or treatment-emergent). These events were evaluated in a comprehensive fashion and
included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg
pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion
in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within
6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6.0 % (21/349) in comparator-treated patients. The
majority of these events were mild or moderate in intensity. All musculoskeletal events
occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30
days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients
than control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-
treated patients were more likely to report more than one event and on more than one
occasion compared to control patients. These events occurred in all age groups and the rates
were consistently higher in the ciprofloxacin group compared to the control group. At the end
of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335)
in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during
treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A
diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from
ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical
intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
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≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin
group versus 31% (109/349) in the comparator group. The most frequent events were
gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of
comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to
an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4%
(5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental
injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also
occur in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic
necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression
(life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia,
myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration
(serum),
potassium
elevation
(serum),
prothrombin
time
prolongation
or
decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or
after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-
Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis,
triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
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Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is
removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into
a larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See
Preparation of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
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Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human
populations,
see
INHALATIONAL
ANTHRAX
–
ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and
table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal
excretion; however, the drug is also metabolized and partially cleared through the biliary
system of the liver and through the intestine. These alternative pathways of drug elimination
appear to compensate for the reduced renal excretion in patients with renal impairment.
Nonetheless, some modification of dosage is recommended for patients with severe renal
dysfunction. The following table provides dosage guidelines for use in patients with renal
impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
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Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An
increased incidence of adverse events compared to controls, including events related to joints
and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial,
pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every
8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the
discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
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For current labeling information, please visit https://www.fda.gov/drugsatfda
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal
insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–
2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be
diluted and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL:
manufactured by Bayer HealthCare LLC and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Abbott
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin
(approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs)
given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric
dose based upon comparative plasma AUCs), no effects on joints were observed. This dose
was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
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and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-
dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for
animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-
treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
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Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for
treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was conducted in the US,
Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of
therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological
safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure
or TOC). The Per Protocol population had a causative organism(s) with protocol specified
colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
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Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs
for Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline,
and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for
clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after
prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology
information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516 USA
Rx Only
08724752, R.6
4/04
©2004 Bayer Pharmaceuticals Corporation
12318
58-7295
BAY q 3939
5202-4-A-U.S.-12
Printed In U.S.A.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-847/SLR-028, SLR-029, SLR-031
NDA 19-857/SLR-033, SLR-034, SLR-036
Page 9
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|
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2025-02-12T13:46:06.035117
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19847s028,029,031,19857s033,034,036lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 29}
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CIPRO®
(ciprofloxacin hydrochloride)
TABLETS
CIPRO®
(ciprofloxacin*)
ORAL SUSPENSION
Anthrax draft
1/6/05
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO®
Tablets and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by bacteria.
DESCRIPTION
CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light
yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is
C17H18FN3O3•HCl•H2O and its chemical structure is as follows:
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light
yellow crystalline substance and its chemical structure is as follows:
CIPRO film-coated tablets are available in 100 mg, 250 mg, 500 mg and 750 mg (ciprofloxacin
equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are
cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate,
hypromellose, titanium dioxide, polyethylene glycol and water.
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly
yellowish suspension with strawberry flavor which may contain yellow-orange droplets. It is
composed of ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See
instructions for USE/HANDLING). The components of the suspension have the following
compositions:
Microcapsules - ciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20.
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
CLINICAL PHARMACOLOGY
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal
tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss
by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are
shown in the chart for the 250 mg to 1000 mg dose range.
Dose
(mg)
Maximum
Serum Concentration
(µg/mL)
Area
Under Curve (AUC)
(µg•hr/mL)
250
1.2
4.8
500
2.4
11.6
750
4.3
20.2
1000
5.4
30.8
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimi-
nation half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations
increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been
shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400
mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed
with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that
produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
Steady-state Pharmacokinetic Parameters
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
AUC (µg•hr/mL)
q12h, P.O.
13.7a
q12h, I.V.
12.7a
q12h, P.O.
31.6b
q8h, I.V.
32.9c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
aAUC 0-12h
bAUC 24h=AUC0-12h x 2
cAUC 24h=AUC0-8h x 3
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high
enough to cause significant protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations
often exceed serum concentrations in both men and women, particularly in genital tissue including the
prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of
the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the
cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
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Metabolism: Four metabolites have been identified in human urine which together account for approxi-
mately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than
unchanged ciprofloxacin.
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL during
the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion
of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin,
which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120
mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately
20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from
either biliary clearance or transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in the
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather
than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The
overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The
pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Concurrent
administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the
bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other
adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See PRECAUTIONS.)
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the
increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These
differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
acute hepatic insufficiency, however, have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
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age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) 5% and
10% Oral Suspension.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Campylobacter jejuni
Proteus mirabilis
Citrobacter diversus
Proteus vulgaris
Citrobacter freundii
Providencia rettgeri
Enterobacter cloacae
Providencia stuartii
Escherichia coli
Pseudomonas aeruginosa
Haemophilus influenzae
Salmonella typhi
Haemophilus parainfluenzae
Serratia marcescens
Klebsiella pneumoniae
Shigella boydii
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Moraxella catarrhalis
Shigella dysenteriae
Morganella morganii
Shigella flexneri
Neisseria gonorrhoeae
Shigella sonnei
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains only)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Pasteurella multocida
Aeromonas hydrophila
Salmonella enteritidis
Edwardsiella tarda
Vibrio cholerae
Enterobacter aerogenes
Vibrio parahaemolyticus
Klebsiella oxytoca
Vibrio vulnificus
Legionella pneumophila
Yersinia enterocolitica
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus
parainfluenzae, and Neisseria gonorrhoeaea:
MIC (µg/mL)
Interpretation
≤1
Susceptible
(S)
2
Intermediate (I)
≥4
Resistant
(R)
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
MIC (µg/mL)
Interpretation
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≤1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
MIC (µg/mL)
Interpretation
≤ 0.06
Susceptible
(S)
0.12 – 0.5
Intermediate (I)
≥1
Resistant
(R)
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
growth supplement.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
N. gonorrhoeaeb
ATCC 49226
0.001 – 0.008
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
bThis quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution
procedure using GC agar base and 1% defined growth supplement.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus
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parainfluenzae, and Neisseria gonorrhoeaea:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 – 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using
Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
Zone Diameter (mm)
Interpretation
≥ 41
Susceptible
(S)
28 – 40
Intermediate (I)
≤ 27
Resistant
(R)
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined
growth supplement.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30 – 40
H. influenzaea
ATCC 49247
34 – 42
N. gonorrhoeaeb
ATCC 49226
48 – 58
P. aeruginosa
ATCC 27853
25 – 33
S. aureus
ATCC 25923
22 – 30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226
performed by disk diffusion using GC agar base and 1% defined growth supplement.
INDICATIONS AND USAGE
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus
epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
saprophyticus.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the
treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
morganii,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
Staphylococcus
aureus
(methicillin-susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
Shigella boydii †, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial
therapy is indicated.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been
demonstrated.
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
significant outcome, efficacy was studied in fewer than 10 patients.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in
order to isolate and identify organisms causing infection and to determine their susceptibility to
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
results become available appropriate therapy should be continued. As with other drugs, some strains of
Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin.
Culture and susceptibility testing performed periodically during therapy will provide information not
only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial
resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by susceptible bacteria. When culture and susceptibility information are available, they should
be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
CIPRO (ciprofloxacin hydrochloride) is contraindicated in persons with a history of hypersensitivity to
ciprofloxacin or any member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus,
and respiratory failure. Although similar serious adverse effects have been reported in patients
receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin
cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be
administered as indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along
with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded.
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of
hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to
life-threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures
should be initiated. Mild cases of pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases, consideration should be given to
management with fluids and electrolytes, protein supplementation, and treatment with an
antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis
should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
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surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in
patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be
discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest
and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after
three months.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in patients who are exposed to direct sunlight while receiving some members of the
quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if
phototoxicity occurs.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Information for Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be
taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
other antibacterial drugs in the future.
• that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
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For current labeling information, please visit https://www.fda.gov/drugsatfda
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, or with other
products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours
before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products
(like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be
significantly reduced; however, ciprofloxacin may be taken with a meal that contains these products.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to
discontinue therapy if phototoxicity occurs.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience
pain, inflammation, or rupture of a tendon.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease its
absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND
ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions,
resulted in severe hypoglycemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomi-
tantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might
increase the risk of methotrexate associated toxic reactions. Therefore, patients under
methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is
indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to
reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin, and the test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maxi-
mum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
weeks in mice treated concomitantly with UVA and other quinolones.3
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In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance
of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and
well-controlled studies in pregnant women. An expert review of published data on experiences with
ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that
therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and
quality of data=fair), but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to
fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during
gestation.8 In utero exposure to fluoroquinolones during embryogenesis was not associated
with increased risk of major malformations. The reported rates of major congenital
malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group
(background incidence of major malformations is 1-5%). Rates of spontaneous abortions,
prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during
pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and
100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based
upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended
therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing
joints
of
juvenile
animals
resulting
in
lameness.
(See
ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including events related to joints and/or surrounding tissues. The
rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless
of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age
were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin
encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65
years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or
This label may not be the latest approved by FDA.
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effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled
out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
reactions may be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function. However, since some
older individuals experience reduced renal function by virtue of their advanced age, care should be taken
in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.0% of
orally treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are listed
below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in
extremities, injection site reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis,
phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression,
paresthesia, abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain,
flare up of gout
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary
retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
hemoptysis, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity,
flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands,
cutaneous candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception,
overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad
taste, chromatopsia
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In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during
treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A
diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from
ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical
intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
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95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anaphylactic reactions, anosmia, candiduria, cholesterol
elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme,
exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
failure, hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis
(The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial
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treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome,
taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis, triglyceride
elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also
INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION.)
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
regard to drug relationship are listed below:
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
(0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%),
elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
observed and given supportive treatment, including monitoring of renal function and administration of
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
is removed from the body after hemodialysis or peritoneal dialysis.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats,
and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral
doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs
observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed
in these animals, occurring 10-14 days after dosing.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the Dosage
Guidelines table.
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s
host-defense mechanisms, and the status of renal function and hepatic function.
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
however, for severe and complicated infections more prolonged therapy may be required.
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
solution, or other products containing calcium, iron or zinc.
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ADULT DOSAGE GUIDELINES
Infection
Severity
Dose
Frequency
Usual Durations†
Urinary Tract
Acute Uncomplicated
100 mg or 250 mg
q 12 h
3 Days
Mild/Moderate
250 mg
q 12 h
7 to 14 Days
Severe/Complicated
500 mg
q 12 h
7 to 14 Days
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 Days
Prostatitis
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 Days
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 Days
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 Days
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 Days
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 Days
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
Gonococcal Infections
Inhalational anthrax
500 mg
q 12 h
60 Days
(post-exposure)**
* used in conjunction with metronidazole
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of
infection have disappeared, except for inhalational anthrax (post-exposure).
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in
humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION.
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the
physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens).
Equivalent AUC Dosing Regimens
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
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through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended, particularly for patients with severe renal dysfunction. The following table provides
dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dose
> 50
See Usual Dosage.
30 – 50
250 – 500 mg q 12 h
5 – 29
250 – 500 mg q 18 h
Patients on hemodialysis
250 – 500 mg q 24 h (after dialysis)
or Peritoneal dialysis
When only the serum creatinine concentration is known, the following formula may be used to estimate
creatinine clearance.
Men: Creatinine clearance (mL/min) =
Weight (kg) x (140 - age)
72 x serum creatinine (mg/dL)
Women: 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered
at the intervals noted above. Patients should be carefully monitored.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
Guidelines table. An increased incidence of adverse events compared to controls, including
events related to joints and/or surrounding tissues, has been observed. (See ADVERSE
REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial,
pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8
hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of
the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total Duration
Complicated
Urinary Tract
or
Pyelonephritis
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
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(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
HOW SUPPLIED
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
tablets containing 100 mg or 250 mg ciprofloxacin. The 100 mg tablet is coded with the word “CIPRO”
on one side and “100” on the reverse side. The 250 mg tablet is coded with the word “CIPRO” on one
side and “250” on the reverse side. CIPRO is also available as capsule shaped, slightly yellowish
film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet is coded with the
word “CIPRO” on one side and “500” on the reverse side. The 750 mg tablet is coded with the word
“CIPRO” on one side and “750” on the reverse side. CIPRO 250 mg, 500 mg, and 750 mg are available
in bottles of 50, 100, and Unit Dose packages of 100. The 100 mg strength is available only as CIPRO
Cystitis pack containing 6 tablets for use only in female patients with acute uncomplicated cystitis.
Strength
NDC Code
Tablet Identification
Bottles of 50:
750 mg
NDC 0026-8514-50
CIPRO 750
Bottles of 100:
250 mg
NDC 0026-8512-51
CIPRO 250
500 mg
NDC 0026-8513-51
CIPRO 500
Unit Dose
Package of 100:
250 mg
NDC 0026-8512-48
CIPRO 250
500 mg
NDC 0026-8513-48
CIPRO 500
750 mg
NDC 0026-8514-48
CIPRO 750
Cystitis
Package of 6:
100 mg
NDC 0026-8511-06
CIPRO 100
Store below 30°C (86°F).
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
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pharmacist. See Instructions To The Pharmacist For Use/Handling.
Total volume
Ciprofloxacin
Ciprofloxacin
Strengths
after reconstitution
Concentration
contents per bottle
NDC Code
5%
100 mL
250 mg/5 mL
5,000 mg
0026-8551-36
10%
100 mL
500 mg/5 mL
10,000 mg
0026-8553-36
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
teaspoon is provided for the patient.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin
(approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs)
given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric
dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was
also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In
another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent
them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release, since they are
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
produces hypotension but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina,
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Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days
Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by
Patient at 5 to 9 Days
Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
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information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day drug administration period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
which must be combined prior to dispensing.
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of
ciprofloxacin.
Appropriate Dosing Volumes of the Oral Suspensions:
Dose
5%
10%
250 mg
5 mL
2.5 mL
500 mg
10 mL
5 mL
750 mg
15 mL
7.5 mL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation of the suspension:
CIPRO Oral Suspension should not be administered through feeding tubes due to its
physical characteristics.
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
approximately 15 seconds and not to chew the microcapsules.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National
Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk
Susceptibility Tests-Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective
Drug and Dermatological Drug Product’s Advisory Committee meeting, March 31, 1993,
Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff,
HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. 4. 21 CFR 314.510
(Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses). 5. Kelly DJ,
et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. 6. Friedlander AM, et al.
1. The small bottle
contains the
microcapsules, the
large bottle
contains the
diluent.
3. Pour the
microcapsules
completely into the
larger bottle of
diluent. Do not add
water to the
suspension.
2. Open both bottles.
Child-proof cap: Press
down according to
instructions on the cap
while turning to the
left.
4. Remove the top layer
of the diluent bottle
label (to reveal the
CIPRO Oral
Suspension label).
Close the large bottle
completely according
to the directions on the
cap and shake
vigorously for about
15 seconds. The
suspension is ready for
use.
1.
2.
3.
4.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993;
167:1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians
(TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8. Loebstein R,
Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a
multicenter
prospective
controlled
study.
Antimicrob
Agents
Chemother.
1998;42(6):1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome
after prenatal quinolone exposure. Evaluation of a case registry of the European network of
teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
Patient Information About:
CIPRO®
(ciprofloxacin hydrochloride) TABLETS
CIPRO®
(ciprofloxacin*) ORAL SUSPENSION
This section contains important patient information about CIPRO (ciprofloxacin hydrochloride)
Tablets and CIPRO (ciprofloxacin*) Oral Suspension and should be read completely before you begin
treatment. This section does not take the place of discussion with your doctor or health care
professional about your medical condition or your treatment. This section does not list all benefits and
risks of CIPRO. If you have any concerns about your condition or your medicine, ask your doctor. Only
your doctor can determine if CIPRO is right for you.
What is CIPRO?
CIPRO is an antibiotic used to treat bladder, kidney, prostate, cervix, stomach, intestine, lung, sinus,
bone, and skin infections caused by certain germs called bacteria. CIPRO kills many types of bacteria
that can infect these areas of the body. CIPRO has been shown in a large number of clinical trials to be
safe and effective for the treatment of bacterial infections.
Sometimes viruses rather than bacteria may infect the lungs and sinuses (for example the common
cold). CIPRO, like all other antibiotics, does not kill viruses. You should contact your doctor if your
condition is not improving while taking CIPRO.
CIPRO Tablets are white to slightly yellow in color and are available in 100 mg, 250 mg, 500 mg and
750 mg strengths. CIPRO Oral Suspension is white to slightly yellow in color and is available in con-
centrations of 250 mg per teaspoon (5%) and 500 mg per teaspoon (10%).
How and when should I take CIPRO?
CIPRO Tablets:
Unless directed otherwise by your physician, CIPRO should be taken twice a day at approximately the
same time, in the morning and in the evening. CIPRO can be taken with food or on an empty stomach.
CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone;
however, CIPRO may be taken with a meal that contains these products.
You should take CIPRO for as long as your doctor prescribes it, even after you start to feel better.
Stopping an antibiotic too early may result in failure to cure your infection. Do not take a double dose
of CIPRO even if you miss a dose by mistake.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Oral Suspension:
Take CIPRO Oral Suspension in the same way as above. In addition, remember to shake the bottle vig-
orously each time before use for approximately 15 seconds to make sure the suspension is mixed well.
Be sure to swallow the required amount of suspension. Do not chew the microcapsules. Close the
bottle completely after use. The product can be used for 14 days when stored in a refrigerator or at
room temperature. After treatment has been completed, any remaining suspension should be discarded.
Who should not take CIPRO?
You should not take CIPRO if you have ever had a severe reaction to any of the group of antibiotics
known as “quinolones”.
CIPRO is not recommended during pregnancy or nursing, as the effects of CIPRO on the unborn child
or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking CIPRO
talk to your doctor before taking this medication.
Due to possible side effects, CIPRO is not recommended for persons less than 18 years of age
except for specific serious infections, such as complicated urinary tract infections.
What are the possible side effects of CIPRO?
CIPRO is generally well tolerated. The most common side effects, which are usually mild, include
nausea, diarrhea, vomiting, and abdominal pain/discomfort. If diarrhea persists, call your health care
professional.
Rare cases of allergic reactions have been reported in patients receiving quinolones, including CIPRO,
even after just one dose. If you develop hives, difficulty breathing, or other symptoms of a severe
allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should stop
taking CIPRO and call your health care professional.
Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light
such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet light
while you are taking CIPRO.
You should be careful about driving or operating machinery until you are sure CIPRO is not causing
dizziness. Convulsions have been reported in patients receiving quinolone antibiotics including
ciprofloxacin. Be sure to let your physician know if you have a history of convulsions. Quinolones,
including ciprofloxacin, have been rarely associated with other central nervous system events
including confusion, tremors, hallucinations, and depression.
CIPRO has been rarely associated with inflammation of tendons. If you experience pain, swelling or
rupture of a tendon, you should stop taking CIPRO and call your health care professional.
CIPRO has been associated with an increased rate of side effects with joints and surrounding
structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform
their child’s physician if the child has a history of joint-related problems before taking this drug.
Parents of pediatric patients should also notify their child’s physician of any joint related
problems that occur during or following CIPRO therapy.
If you notice any side effects not mentioned in this section, or if you have any concerns about side
effects you may be experiencing, please inform your health care professional.
What about other medications I am taking?
CIPRO can affect how other medicines work. Tell your doctor about all other prescription and
non-prescription medicines or supplements you are taking. This is especially important if you are
taking theophylline. Other medications including warfarin, glyburide, and phenytoin may also interact
with CIPRO.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium,
aluminum, iron or zinc can interfere with the absorption of CIPRO and may prevent it from working.
Other medications such as sulcrafate and Videx® (didanosine) chewable/buffered tablets or pediatric
powder may also stop CIPRO from working. You should take CIPRO either 2 hours before or 6 hours
after taking these products.
What if I have been prescribed CIPRO for possible anthrax exposure?
CIPRO has been approved to reduce the chance of developing anthrax infection following exposure to
the anthrax bacteria. In general, CIPRO is not recommended for children; however, it is approved for
use in patients younger than 18 years old for anthrax exposure. If you are pregnant, or plan to become
pregnant while taking CIPRO, you and your doctor should discuss if the benefits of taking CIPRO for
anthrax outweigh the risks.
CIPRO is generally well tolerated. Side effects that may occur during treatment to prevent anthrax
might be acceptable due to the seriousness of the disease. You and your doctor should discuss the risks
of not taking your medicine against the risks of experiencing side effects.
CIPRO can cause dizziness, confusion, or other similar side effects in some people. Therefore, it is
important to know how CIPRO affects you before driving a car or performing other activities that
require you to be alert and coordinated such as operating machinery.
Your doctor has prescribed CIPRO only for you. Do not give it to other people. Do not use it for a
condition for which it was not prescribed. You should take your CIPRO for as long as your doctor
prescribes it; stopping CIPRO too early may result in failure to prevent anthrax.
Remember:
Do not give CIPRO to anyone other than the person for whom it was prescribed.
Take your dose of CIPRO in the morning and in the evening.
Complete the course of CIPRO even if you are feeling better.
Keep CIPRO and all medications out of reach of children.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Rx Only
xxxxxxxxx
1/05
Bay o 9867
©2005 Bayer Pharmaceuticals Corporation
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy.
Cipro (ciprofloxacin HCl) Tablets Made in U.S.A. and Germany
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
anthraxdraft
1/6/05
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes
every 12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of
400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral
dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into
cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations.
Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to
serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in
patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin
and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin,
probenecid, and piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reports from the laboratory providing results of the standard single-disk susceptibility test with
a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or
Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
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pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for
the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus
(methicillin susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy
with CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
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therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to
ciprofloxacin or any member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
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some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin
cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to
life-threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In
moderate to severe cases, consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically effective against C.
difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased
in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be
discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest
and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
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(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of the
quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or
not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience
pain, inflammation, or rupture of a tendon.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
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due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but
the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg
(0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively)
and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral
ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest
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recommended therapeutic dose based upon mg/m2) produced gastrointestinal toxicity resulting
in maternal weight loss and an increased incidence of abortion, but no teratogenicity was
observed at either dose level. After intravenous administration of doses up to 20 mg/kg
(approximately 0.3-times the highest recommended therapeutic dose based upon mg/m2) no
maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See
WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure),
see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including those related to joints and/or surrounding tissues. The rates
of these events in pediatric patients with complicated urinary tract infection and pyelonephritis
within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents.
The rates of these events occurring at any time up to the one year follow-up were 13.7%
(46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug
relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of
age were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
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motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney,
and the risk of adverse reactions may be greater in patients with impaired renal function. No
alteration of dosage is necessary for patients greater than 65 years of age with normal renal
function. However, since some older individuals experience reduced renal function by virtue of
their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported
were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V.
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as
local skin reactions which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
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hypertension,
hypotension,
angina
pectoris,
atrial
flutter,
ventricular
ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions,
erythema
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis,
angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever, chills,
flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration, hyperpigmentation,
erythema nodosum, thrombophlebitis, burning, paresthesia, erythema, swelling, photosensitivity (See
WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during
treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A
diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from
ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical
intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic necrosis,
hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression (life
threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia,
myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life
threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum), potassium
elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis
(toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis,
tendon rupture, torsade de pointes, toxic epidermal necrolysis, triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also
INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is
removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a
larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation
of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL
ANTHRAX
–
ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and
table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the
liver and through the intestine. These alternative pathways of drug elimination appear to
compensate for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended for patients with severe renal dysfunction. The
following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased
incidence of adverse events compared to controls, including events related to joints and/or
surrounding tissues, has been observed. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial,
pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8
hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of
the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of
1–2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL:
manufactured by Bayer HealthCare LLC and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Abbott
Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin
(approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs)
given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric
dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was
also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In
another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent
them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric
patients
receiving
oral
and
intravenous
regimens.
(See
DOSAGE
AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA,
January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville,
MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for
Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and
ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis
1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians
(TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8. Loebstein R, Addis
A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter
prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339. 9. Schaefer C,
Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a
case registry of the European network of teratology information services (ENTIS). Eur J Obstet
Gynecol Reprod Biol. 1996;69:83-89.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516 USA
Rx Only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
xxxxxxxx
1/05
©2005 Bayer Pharmaceuticals Corporation
BAY q 3939
5202-4-A-U.S.-12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:06.645409
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/19537s052,19847s030,19857s035,20780s016lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
11,768
|
CIPRO®
1
(ciprofloxacin hydrochloride)
2
TABLETS
3
CIPRO®
4
(ciprofloxacin*)
5
ORAL SUSPENSION
6
7
XXXXXXXX 3/25/04
8
9
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
10
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
11
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to
12
be caused by bacteria.
13
14
DESCRIPTION
15
CIPRO® (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
16
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
17
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-
18
dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow
19
crystalline
substance
with
a
molecular
weight
of
385.8.
Its
empirical
formula
is
20
C17H18FN3O3•HCl•H2O and its chemical structure is as follows:
21
22
23
24
25
26
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
27
acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish
28
to light yellow crystalline substance and its chemical structure is as follows:
29
30
31
32
33
34
CIPRO film-coated tablets are available in 100 mg, 250 mg, 500 mg and 750 mg (ciprofloxacin
35
equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients
36
are cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate,
37
hypromellose, titanium dioxide, polyethylene glycol and water.
38
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
39
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish
40
suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of
41
ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See instructions for
42
USE/HANDLING). The components of the suspension have the following compositions:
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Microcapsules - ciprofloxacin, povidone, methacrylic acid copolymer, hypromellose, magnesium
44
stearate, and Polysorbate 20.
45
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
46
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
47
CLINICAL PHARMACOLOGY
48
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the
49
gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with
50
no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area
51
under the curve are shown in the chart for the 250 mg to 1000 mg dose range.
52
53
Maximum
Area
54
Dose
Serum Concentration
Under Curve (AUC)
55
(mg)
(µg/mL)
(µg•hr/mL)
56
250
1.2
4.8
57
500
2.4
11.6
58
750
4.3
20.2
59
1000
5.4
30.8
60
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
61
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum
62
elimination half-life in subjects with normal renal function is approximately 4 hours. Serum
63
concentrations increase proportionately with doses up to 1000 mg.
64
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
65
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
66
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has
67
been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion
68
of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that
69
observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC
70
equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
71
72
Steady-state Pharmacokinetic Parameters
73
Following Multiple Oral and I.V. Doses
74
Parameters
500 mg
400 mg
750 mg
400
75
mg
76
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h,
77
I.V.
78
AUC (µg•hr/mL)
13.7a
12.7a
31.6b
32.9c
79
Cmax (µg/mL)
2.97
4.56
3.59
4.07
80
aAUC 0-12h
81
bAUC 24h=AUC0-12h x 2
82
cAUC 24h=AUC0-8h x 3
83
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be
84
high enough to cause significant protein binding interactions with other drugs.
85
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue
86
concentrations often exceed serum concentrations in both men and women, particularly in genital tissue
87
including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial
88
secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic
89
secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug
90
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10%
91
of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous
92
humors of the eye.
93
Metabolism: Four metabolites have been identified in human urine which together account for
94
approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active
95
than unchanged ciprofloxacin.
96
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
97
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
98
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL
99
during the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary
100
excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of
101
ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of
102
120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
103
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
104
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
105
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
106
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged
107
drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites.
108
Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This
109
may arise from either biliary clearance or transintestinal elimination.
110
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
111
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
112
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
113
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
114
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in
115
the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing
116
rather than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food.
117
The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected.
118
The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food.
119
Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may
120
reduce the bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
121
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
122
were given concomitantly.
123
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
124
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or
125
other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
126
paraxanthine after caffeine administration. (See PRECAUTIONS.)
127
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
128
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher
129
in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%,
130
the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased
131
renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly.
132
These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
133
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
134
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
135
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
136
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
137
acute hepatic insufficiency, however, have not been fully elucidated.
138
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from
139
4 months to 7 years, the mean Cmax was 2.4 mg/L (range: 1.5 – 3.4 mg/L) and the mean AUC was
140
9.2 mg*h/L (range: 5.8 – 14.9 mg*h/L). There was no apparent age-dependence, and no notable
141
increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who
142
were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mg/L
143
(range: 4.6 – 8.3 mg/L) in 10 children less than 1 year of age; and 7.2 mg/L (range: 4.7 – 11.8 mg/L)
144
in 10 children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range: 11.8 – 32.0
145
mg*h/L) and 16.5 mg*h/L (range: 11.0 – 23.8 mg*h/L) in the respective age groups. These values are
146
within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
147
analysis of pediatric patients with various infections, the predicted mean half-life in children is
148
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
149
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-
150
positive microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the
151
enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
152
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
153
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
154
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
155
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
156
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
157
by multiple step mutations.
158
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
159
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
160
inhibitory concentration (MIC) by more than a factor of 2.
161
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
162
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
163
package insert for CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) 5% and
164
10% Oral Suspension.
165
Aerobic gram-positive microorganisms
166
Enterococcus faecalis (Many strains are only moderately susceptible.)
167
Staphylococcus aureus (methicillin-susceptible strains only)
168
Staphylococcus epidermidis (methicillin-susceptible strains only)
169
Staphylococcus saprophyticus
170
Streptococcus pneumoniae (penicillin-susceptible strains only)
171
Streptococcus pyogenes
172
Aerobic gram-negative microorganisms
173
Campylobacter jejuni
Proteus mirabilis
174
Citrobacter diversus
Proteus vulgaris
175
Citrobacter freundii
Providencia rettgeri
176
Enterobacter cloacae
Providencia stuartii
177
Escherichia coli
Pseudomonas aeruginosa
178
Haemophilus influenzae
Salmonella typhi
179
Haemophilus parainfluenzae
Serratia marcescens
180
Klebsiella pneumoniae
Shigella boydii
181
Moraxella catarrhalis
Shigella dysenteriae
182
Morganella morganii
Shigella flexneri
183
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Neisseria gonorrhoeae
Shigella sonnei
184
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
185
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
186
ANTHRAX – ADDITIONAL INFORMATION).
187
The following in vitro data are available, but their clinical significance is unknown.
188
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
189
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
190
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
191
adequate and well-controlled clinical trials.
192
Aerobic gram-positive microorganisms
193
Staphylococcus haemolyticus
194
Staphylococcus hominis
195
Streptococcus pneumoniae (penicillin-resistant strains only)
196
Aerobic gram-negative microorganisms
197
Acinetobacter Iwoffi
Pasteurella multocida
198
Aeromonas hydrophila
Salmonella enteritidis
199
Edwardsiella tarda
Vibrio cholerae
200
Enterobacter aerogenes
Vibrio parahaemolyticus
201
Klebsiella oxytoca
Vibrio vulnificus
202
Legionella pneumophila
Yersinia enterocolitica
203
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
204
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium
205
difficile.
206
Susceptibility Tests
207
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
208
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
209
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
210
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum
211
concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be
212
interpreted according to the following criteria:
213
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae,
214
and Neisseria gonorrhoeaea:
215
MIC (µg/mL)
Interpretation
216
≤ 1
Susceptible
(S)
217
2
Intermediate
(I)
218
≥ 4
Resistant
(R)
219
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
220
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
221
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
222
MIC (µg/mL)
Interpretation
223
≤ 1
Susceptible
(S)
224
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
225
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
226
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The current absence of data on resistant strains precludes defining any results other than
227
“Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be
228
submitted to a reference laboratory for further testing.
229
For testing Neisseria gonorrhoeaec:
230
MIC (µg/mL)
Interpretation
231
≤ 0.06
Susceptible
(S)
232
0.12 – 0.5
Intermediate
(I)
233
≥ 1
Resistant
(R)
234
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
235
growth supplement.
236
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
237
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
238
indicates that the result should be considered equivocal, and, if the microorganism is not fully
239
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
240
possible clinical applicability in body sites where the drug is physiologically concentrated or in
241
situations where high dosage of drug can be used. This category also provides a buffer zone, which
242
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
243
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
244
compound in the blood reaches the concentrations usually achievable; other therapy should be
245
selected.
246
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
247
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
248
provide the following MIC values:
249
Organism
MIC (µg/mL)
250
E. faecalis
ATCC 29212
0.25 – 2.0
251
E. coli
ATCC 25922
0.004 – 0.015
252
H. influenzaea
ATCC 49247
0.004 – 0.03
253
N. gonorrhoeaeb
ATCC 49226
0.001 – 0.008
254
P. aeruginosa
ATCC 27853
0.25 – 1.0
255
S. aureus
ATCC 29213
0.12 – 0.5
256
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
257
microdilution procedure using Haemophilus Test Medium (HTM)1.
258
bThis quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar
259
dilution procedure using GC agar base and 1% defined growth supplement.
260
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
261
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
262
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure
263
uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
264
ciprofloxacin.
265
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
266
ciprofloxacin disk should be interpreted according to the following criteria:
267
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae,
268
and Neisseria gonorrhoeaea:
269
Zone Diameter (mm)
Interpretation
270
≥ 21
Susceptible
(S)
271
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 – 20
Intermediate
(I)
272
≤ 15
Resistant
(R)
273
aThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-
274
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
275
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
276
Zone Diameter (mm)
Interpretation
277
≥ 21
Susceptible
(S)
278
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
279
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
280
The current absence of data on resistant strains precludes defining any results other than
281
“Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should
282
be submitted to a reference laboratory for further testing.
283
For testing Neisseria gonorrhoeaec:
284
Zone Diameter (mm)
Interpretation
285
≥ 41
Susceptible
(S)
286
28 – 40
Intermediate
(I)
287
≤ 27
Resistant
(R)
288
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1%
289
defined growth supplement.
290
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
291
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
292
As with standardized dilution techniques, diffusion methods require the use of laboratory control
293
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
294
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
295
laboratory test quality control strains:
296
Organism
Zone Diameter (mm)
297
E. coli
ATCC 25922
30 – 40
298
H. influenzaea
ATCC 49247
34 – 42
299
N. gonorrhoeaeb
ATCC 49226
48 – 58
300
P. aeruginosa
ATCC 27853
25 – 33
301
S. aureus
ATCC 25923
22 – 30
302
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
303
Haemophilus Test Medium (HTM)2.
304
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC
305
49226 performed by disk diffusion using GC agar base and 1% defined growth supplement.
306
INDICATIONS AND USAGE
307
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
308
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
309
ADMINISTRATION for specific recommendations.
310
311
Adult Patients:
312
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae,
313
Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter
314
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diversus,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
Staphylococcus
epidermidis,
315
Staphylococcus saprophyticus, or Enterococcus faecalis.
316
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
317
saprophyticus.
318
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
319
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
320
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
321
Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the
322
treatment of acute exacerbations of chronic bronchitis.
323
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment
324
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
325
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
326
catarrhalis.
327
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
328
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
329
morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-
330
susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
331
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
332
aeruginosa.
333
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
334
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
335
fragilis.
336
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
337
Shigella boydii†, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial therapy
338
is indicated.
339
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
340
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not
341
been demonstrated.
342
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
343
344
Pediatric patients (1 to 17 years of age):
345
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
346
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
347
population due to an increased incidence of adverse events compared to controls, including events
348
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
349
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones,
350
is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile
351
animals. (See ANIMAL PHARMACOLOGY.)
352
353
Adult and Pediatric Patients:
354
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
355
exposure to aerosolized Bacillus anthracis.
356
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably
357
likely to predict clinical benefit and provide the basis for this indication.4 (See also,
358
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).
359
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
360
significant outcome, efficacy was studied in fewer than 10 patients.
361
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
362
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
363
administered. Appropriate culture and susceptibility tests should be performed before treatment in
364
order to isolate and identify organisms causing infection and to determine their susceptibility to
365
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
366
results become available appropriate therapy should be continued. As with other drugs, some strains
367
of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with
368
ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide
369
information not only on the therapeutic effect of the antimicrobial agent but also on the possible
370
emergence of bacterial resistance.
371
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
372
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
373
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to
374
be caused by susceptible bacteria. When culture and susceptibility information are available, they
375
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
376
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
377
CONTRAINDICATIONS
378
CIPRO (ciprofloxacin hydrochloride) is contraindicated in persons with a history of hypersensitivity
379
to ciprofloxacin or any member of the quinolone class of antimicrobial agents.
380
WARNINGS
381
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
382
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
383
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
384
385
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
386
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
387
events compared to controls, including events related to joints and/or surrounding tissues, has been
388
observed. (See ADVERSE REACTIONS.)
389
390
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
391
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions
392
of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing
393
joints and other signs of arthropathy in immature animals of various species. (See ANIMAL
394
PHARMACOLOGY.)
395
396
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
397
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
398
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
399
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
400
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
401
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
402
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
403
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
404
risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
405
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
406
and ADVERSE REACTIONS.)
407
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
408
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND
409
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
410
respiratory failure. Although similar serious adverse effects have been reported in patients receiving
411
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
412
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored
413
and dosage adjustments made as appropriate.
414
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
415
some following the first dose, have been reported in patients receiving quinolone therapy. Some
416
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
417
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
418
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine.
419
Oxygen, intravenous steroids, and airway management, including intubation, should be administered
420
as indicated.
421
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
422
necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along
423
with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded.
424
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of
425
hypersensitivity.
426
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
427
antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-
428
threatening. Therefore, it is important to consider this diagnosis in patients who present with
429
diarrhea subsequent to the administration of antibacterial agents.
430
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
431
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
432
“antibiotic-associated colitis.”
433
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
434
initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In
435
moderate to severe cases, consideration should be given to management with fluids and electrolytes,
436
protein supplementation, and treatment with an antibacterial drug clinically effective against C.
437
difficile colitis. Drugs that inhibit peristalsis should be avoided.
438
Tendon Rupture: Ruptures of the shoulder, hand, and Achilles and other tendon ruptures that
439
required surgical repair or resulted in prolonged disability have been reported in patients receiving
440
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that the risk may be
441
increased in patients receiving concomitant corticosteroids, especially in the elderly. Ciprofloxacin
442
should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.
443
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
444
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
445
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
446
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis
447
after three months.
448
PRECAUTIONS
449
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
450
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
451
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
452
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
453
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
454
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
455
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
456
(See WARNINGS, Information for Patients, and Drug Interactions.)
457
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of
458
renal function. (See DOSAGE AND ADMINISTRATION.)
459
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
460
been observed in patients who are exposed to direct sunlight while receiving some members of the
461
quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if
462
phototoxicity occurs.
463
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
464
hematopoietic function, is advisable during prolonged therapy.
465
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
466
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient
467
and increases the risk of the development of drug-resistant bacteria.
468
Information for Patients:
469
Patients should be advised:
470
• that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
471
to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
472
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
473
told that although it is common to feel better early in the course of therapy, the medication should
474
be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
475
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
476
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
477
other antibacterial drugs in the future.
478
• that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
479
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
480
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, or with other
481
products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours
482
before or six hours after taking these products. Ciprofloxacin should not be taken with dairy
483
products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin
484
may be significantly reduced; however, ciprofloxacin may be taken with a meal that contains these
485
products.
486
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
487
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
488
• to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to
489
discontinue therapy if phototoxicity occurs.
490
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they
491
experience pain, inflammation, or rupture of a tendon.
492
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
493
they react to this drug before they operate an automobile or machinery or engage in activities
494
requiring mental alertness or coordination.
495
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
496
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
497
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
498
notify their physician before taking this drug if there is a history of this condition.
499
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
500
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
501
should inform their child’s physician if the child has a history of joint-related problems before
502
taking this drug. Parents of pediatric patients should also notify their child’s physician of any joint-
503
related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
504
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
505
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
506
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
507
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
508
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
509
monitored and dosage adjustments made as appropriate.
510
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
511
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
512
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
513
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
514
tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease
515
its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE
516
AND ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.)
517
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
518
ciprofloxacin.
519
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
520
concomitant ciprofloxacin.
521
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare
522
occasions, resulted in severe hypoglycemia.
523
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
524
creatinine in patients receiving cyclosporine concomitantly.
525
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
526
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
527
prothrombin time or other suitable coagulation tests should be closely monitored.
528
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the
529
level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
530
concomitantly.
531
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
532
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
533
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
534
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
535
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time
536
to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
537
ciprofloxacin.
538
Animal studies have shown that the combination of very high doses of quinolones and certain non-
539
steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.
540
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
541
conducted with ciprofloxacin, and the test results are listed below:
542
Salmonella/Microsome Test (Negative)
543
E. coli DNA Repair Assay (Negative)
544
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
545
Chinese Hamster V79 Cell HGPRT Test (Negative)
546
Syrian Hamster Embryo Cell Transformation Assay (Negative)
547
Saccharomyces cerevisiae Point Mutation Assay (Negative)
548
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
549
Rat Hepatocyte DNA Repair Assay (Positive)
550
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
551
results:
552
Rat Hepatocyte DNA Repair Assay
553
Micronucleus Test (Mice)
554
Dominant Lethal Test (Mice)
555
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
556
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
557
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
558
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
559
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
560
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
561
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
562
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to
563
maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
564
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
565
weeks in mice treated concomitantly with UVA and other quinolones.3
566
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There
567
are no data from similar models using pigmented mice and/or fully haired mice. The clinical
568
significance of these findings to humans is unknown.
569
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-
570
times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
571
impairment.
572
Pregnancy: Teratogenic Effects. Pregnancy Category C:
573
There are no adequate and well-controlled studies in pregnant women. An expert review of published
574
data on experiences with ciprofloxacin use during pregnancy by TERIS – the Teratogen Information
575
System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial
576
teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no
577
risk.7
578
A controlled prospective observational study followed 200 women exposed to fluoroquinolones
579
(52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero
580
exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major
581
malformations. The reported rates of major congenital malformations were 2.2% for the
582
fluoroquinolone group and 2.6% for the control group (background incidence of major malformations
583
is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the
584
groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in
585
the ciprofloxacin exposed children.
586
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure
587
(93% first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester.
588
The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones
589
overall were both within background incidence ranges. No specific patterns of congenital
590
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
abnormalities were found. The study did not reveal any clear adverse reactions due to in utero
591
exposure to ciprofloxacin.
592
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
593
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
594
studies, of which most experience is from short term, first trimester exposure, are insufficient to
595
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
596
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
597
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
598
(see WARNINGS).
599
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
600
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
601
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose
602
levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic
603
dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an
604
increased incidence of abortion, but no teratogenicity was observed at either dose level. After
605
intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
606
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no
607
embryotoxicity or teratogenicity was observed. (See WARNINGS.)
608
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed
609
by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants
610
nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing
611
or to discontinue the drug, taking into account the importance of the drug to the mother.
612
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
613
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
614
PHARMACOLOGY.)
615
Inhalational Anthrax (Post-Exposure)
616
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-
617
benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
618
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE
619
AND
ADMINISTRATION
and
INHALATIONAL
ANTHRAX
–
ADDITIONAL
620
INFORMATION.
621
622
Complicated Urinary Tract Infection and Pyelonephritis
623
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
624
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice
625
in the pediatric population due to an increased incidence of adverse events compared to the controls,
626
including events related to joints and/or surrounding tissues. The rates of these events in pediatric
627
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up
628
were 9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at
629
any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate
630
of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the
631
ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS
632
and CLINICAL STUDIES.)
633
Cystic Fibrosis
634
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
635
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
636
fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
637
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
638
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
639
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
640
monitoring in the study included periodic range of motion examinations and gait assessments by
641
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
642
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
643
of repeated exposure to ciprofloxacin.
644
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
645
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
646
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
647
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
648
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
649
patients developed arthritis of the knee nine days after a ten day course of treatment with
650
ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other
651
abnormalities eight months after treatment. However, the relationship of this event to the patient’s
652
course of ciprofloxacin can not be definitively determined, particularly since patients with cystic
653
fibrosis may develop arthralgias/arthritis as part of their underlying disease process.
654
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
655
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater
656
than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall
657
differences in safety or effectiveness were observed between these subjects and younger subjects, and
658
other reported clinical experience has not identified differences in responses between the elderly and
659
younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled
660
out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
661
reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary
662
for patients greater than 65 years of age with normal renal function. However, since some older
663
individuals experience reduced renal function by virtue of their advanced age, care should be taken in
664
dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See
665
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
666
ADVERSE REACTIONS
667
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
668
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
669
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
670
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.0% of orally
671
treated patients.
672
The most frequently reported drug related events, from clinical trials of all formulations, all dosages,
673
all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
674
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
675
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are
676
listed below.
677
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities,
678
injection site reaction (ciprofloxacin intravenous)
679
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
680
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis, phlebitis,
681
tachycardia, migraine, hypotension
682
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
683
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
684
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia,
685
abnormal gait, grand mal convulsion
686
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
687
gastrointestinal bleeding, cholestatic jaundice, hepatitis
688
HEMIC/LYMPHATIC: lymphadenopathy, petechia
689
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
690
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare
691
up of gout
692
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention,
693
urethral bleeding, vaginitis, acidosis, breast pain
694
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis,
695
bronchospasm, pulmonary embolism
696
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity, flushing,
697
fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous
698
candidiasis, hyperpigmentation, erythema nodosum, sweating
699
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness
700
of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste,
701
chromatopsia
702
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators
703
to be related to elevated serum levels of theophylline possibly as a result of drug interaction with
704
ciprofloxacin.
705
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
706
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
707
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
708
control drugs.
709
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
710
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
711
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was
712
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
713
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
714
days). The primary objective of the study was to assess musculoskeletal and neurological safety
715
within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
716
comparator-treated patients enrolled.
717
718
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
719
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-
720
emergent). These events were evaluated in a comprehensive fashion and included such conditions as
721
arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain,
722
pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee,
723
elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events
724
were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in comparator-treated
725
patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events
726
occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of
727
end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events.
728
The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless
729
of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were more likely to
730
report more than one event and on more than one occasion compared to control patients. These events
731
occurred in all age groups and the rates were consistently higher in the ciprofloxacin group compared
732
to the control group. At the end of 1 year, the rate of these events reported at any time during that
733
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-
734
treated patients.
735
736
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
737
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
738
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
739
excluded. The patient recovered by 4 months without surgical intervention.
740
741
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
742
743
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
744
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that
745
of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
746
interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the control
747
group.
748
749
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in
750
the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness,
751
nervousness, insomnia, and somnolence.
752
753
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
754
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
755
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
756
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
757
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
758
Discontinuation of drug due to an adverse events were observed in 3% (10/335) of ciprofloxacin-
759
treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at
760
least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%,
761
accidental injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and
762
rash 1.8%.
763
764
In addition to the events reported in pediatric patients in clinical trials, it should be expected that
765
events reported in adults during clinical trials or post-marketing experience may also occur in
766
pediatric patients.
767
768
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
769
marketing experience with quinolones, including ciprofloxacin. Because these events are reported
770
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
771
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
772
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
773
frequency of the reporting, or (3) strength of causal connection to the drug.
774
Agitation, agranulocytosis, albuminuria, anaphylactic reactions, anosmia, candiduria, cholesterol
775
elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme,
776
exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
777
failure, hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
778
marrow depression (life threatening), methemoglobinemia, monoliasis (oral, gastrointestinal, vaginal)
779
myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
780
pancytopenia (life threatening or fatal outcome), phenytoin alteration (serum), potassium elevation
781
(serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
782
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis
783
(toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis,
784
tendon rupture, toxic epidermal necrolysis, triglyceride elevation (serum), twitching, vaginal
785
candidiasis, and vasculitis. (See PRECAUTIONS.)
786
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
787
regard to drug relationship are listed below:
788
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
789
(0.8%), LDH (0.4%), serum bilirubin (0.3%).
790
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated
791
blood platelets (0.1%), pancytopenia (0.1%).
792
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
793
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
794
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
795
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
796
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
797
OVERDOSAGE
798
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
799
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
800
observed and given supportive treatment, including monitoring of renal function and administration of
801
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
802
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
803
is removed from the body after hemodialysis or peritoneal dialysis.
804
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice,
805
rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest
806
oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical
807
signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs.
808
In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was
809
delayed in these animals, occurring 10-14 days after dosing.
810
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
811
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
812
DOSAGE AND ADMINISTRATION - ADULTS
813
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the
814
Dosage Guidelines table.
815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The determination of dosage for any particular patient must take into consideration the severity and
816
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s host-
817
defense mechanisms, and the status of renal function and hepatic function.
818
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
819
however, for severe and complicated infections more prolonged therapy may be required.
820
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
821
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
822
solution, or other products containing calcium, iron or zinc.
823
824
ADULT DOSAGE GUIDELINES
825
Infection
Severity
Dose
Frequency Usual Durations†
826
Urinary Tract
Acute Uncomplicated
100 mg or 250 mg
q 12 h
3 Days
827
Mild/Moderate
250 mg
q 12 h
7 to 14 Days
828
Severe/Complicated
500 mg
q 12 h
7 to 14 Days
829
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 Days
830
Prostatitis
831
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
832
Severe/Complicated
750 mg
q 12 h
7 to 14 days
833
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
834
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 Days
835
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 Days
836
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
837
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
838
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 Days
839
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 Days
840
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 Days
841
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
842
Gonococcal Infections
843
Inhalational anthrax
500 mg
q 12 h
60 Days
844
(post-exposure)**
845
846
847
* used in conjunction with metronidazole
848
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have
849
disappeared, except for inhalational anthrax (post-exposure).
850
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
851
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
852
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various
853
human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
854
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
855
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of
856
the physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing
857
regimens).
858
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Equivalent AUC Dosing Regimens
859
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
860
250 mg Tablet q 12 h
200 mg I.V. q 12 h
861
500 mg Tablet q 12 h
400 mg I.V. q 12 h
862
750 mg Tablet q 12 h
400 mg I.V. q 8 h
863
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
864
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
865
through the intestine. These alternative pathways of drug elimination appear to compensate for the
866
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage
867
is recommended, particularly for patients with severe renal dysfunction. The following table provides
868
dosage guidelines for use in patients with renal impairment:
869
RECOMMENDED STARTING AND MAINTENANCE DOSES
870
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
871
Creatinine Clearance (mL/min)
Dose
872
> 50
See Usual Dosage.
873
30 – 50
250 – 500 mg q 12 h
874
5 – 29
250 – 500 mg q 18 h
875
Patients on hemodialysis
250–500 mg q 24 h (after dialysis)
876
or Peritoneal dialysis)
877
When only the serum creatinine concentration is known, the following formula may be used to
878
estimate creatinine clearance.
879
Men: Creatinine clearance (mL/min) = Weight (kg) x (140 - age)
880
72 x serum creatinine (mg/dL)
881
Women: 0.85 x the value calculated for men.
882
The serum creatinine should represent a steady state of renal function.
883
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be
884
administered at the intervals noted above. Patients should be carefully monitored.
885
DOSAGE AND ADMINISTRATION - PEDIATRICS
886
887
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
888
Guidelines table. An increased incidence of adverse events compared to controls, including events
889
related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS and
890
CLINICAL STUDIES.)
891
892
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
893
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
894
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
895
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
896
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
897
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 8 hours
Complicated
Urinary Tract or
Pyelonephritis
(patients from 1
to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 12
hours
10-21
days*
Intravenous
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was
898
determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
899
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
900
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved
901
in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations
902
in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
903
904
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
905
complicated urinary tract infection and pyelonephritis. No information is available on dosing
906
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e.,
907
creatinine clearance of < 50 mL/min/1.73m2).
908
909
HOW SUPPLIED
910
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
911
tablets containing 100 mg or 250 mg ciprofloxacin. The 100 mg tablet is coded with the word
912
“CIPRO” on one side and “100” on the reverse side. The 250 mg tablet is coded with the word
913
“CIPRO” on one side and “250” on the reverse side. CIPRO is also available as capsule shaped,
914
slightly yellowish film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet
915
is coded with the word “CIPRO” on one side and “500” on the reverse side. The 750 mg tablet is
916
coded with the word “CIPRO” on one side and “750” on the reverse side. CIPRO 250 mg, 500 mg,
917
and 750 mg are available in bottles of 50, 100, and Unit Dose packages of 100. The 100 mg strength is
918
available only as CIPRO Cystitis pack containing 6 tablets for use only in female patients with acute
919
uncomplicated cystitis.
920
Strength
NDC Code
Tablet Identification
921
Bottles of 50:
750 mg
NDC 0026-8514-50
CIPRO 750
922
Bottles of 100:
250 mg
NDC 0026-8512-51
CIPRO 250
923
500 mg
NDC 0026-8513-51
CIPRO 500
924
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Unit Dose
925
Package of 100:
250 mg
NDC 0026-8512-48
CIPRO 250
926
500 mg
NDC 0026-8513-48
CIPRO 500
927
750 mg
NDC 0026-8514-48
CIPRO 750
928
Cystitis
929
Package of 6:
100 mg
NDC 0026-8511-06
CIPRO 100
930
Store below 30°C (86°F).
931
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
932
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
933
pharmacist. See Instructions To The Pharmacist For Use/Handling.
934
Total volume
Ciprofloxacin
Ciprofloxacin
935
Strengths
after reconstitution
Concentration
contents per bottle
NDC Code
936
5%
100 mL
250 mg/5 mL
5,000 mg
0026-8551-36
937
10%
100 mL
500 mg/5 mL
10,000 mg
0026-8553-36
938
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
939
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
940
teaspoon is provided for the patient.
941
ANIMAL PHARMACOLOGY
942
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
943
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
944
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
945
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
946
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
947
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
948
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
949
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
950
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
951
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
952
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
953
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
954
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
955
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human
956
urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single
957
oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose
958
based upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological
959
changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same
960
duration (approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
961
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
962
hypotensive effects. These effects are considered to be related to histamine release, since they are
963
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
964
produces hypotension but the effect in this species is inconsistent and less pronounced.
965
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
966
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
967
quinolones.
968
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
969
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL STUDIES
970
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
971
972
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
973
population due to an increased incidence of adverse events compared to controls, including events
974
related to joints and/or surrounding tissues.
975
Ciprofloxacin, administered I.V. and /or orally, was compared to a cephalosporin for treatment of
976
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of
977
age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa
978
Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration
979
of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to
980
assess musculoskeletal and neurological safety.
981
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
982
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
983
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline,
984
no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
985
986
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
987
between ciprofloxacin and the comparator group as shown below.
988
989
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
990
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic
Eradication
of
the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
991
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or
992
new infections.
993
994
INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
995
INFORMATION
996
The mean serum concentrations of ciprofloxacin associated with a statistically significant
997
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
998
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
999
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
1000
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
1001
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
1002
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
1003
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
1004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
1005
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
1006
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
1007
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
1008
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
1009
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
1010
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
1011
provide the basis for this indication.4
1012
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
1013
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
1014
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
1015
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-
1016
dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough
1017
concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for
1018
animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
1019
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-
1020
treated animal that died of anthrax did so following the 30-day drug administration period.6
1021
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
1022
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
1023
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
1024
which must be combined prior to dispensing.
1025
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
1026
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of ciprofloxacin.
1027
Appropriate Dosing Volumes of the Oral Suspensions:
1028
Dose
5%
10%
1029
250 mg
5 mL
2.5 mL
1030
500 mg
10 mL
5 mL
1031
750 mg
15 mL
7.5 mL
1032
Preparation of the suspension:
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1. The small bottle
contains the
microcapsules, the
large bottle contains
the diluent.
3. Pour the
microcapsules
completely into the
larger bottle of
diluent. Do not add
water to the
suspension.
2. Open both bottles.
Child-proof cap: Press
down according to
instructions on the cap
while turning to the left.
4. Remove the top layer of
the diluent bottle label
(to reveal the CIPRO
Oral Suspension label).
Close the large bottle
completely according to
the directions on the cap
and shake vigorously for
about 15 seconds. The
suspension is ready for
use.
1.
2.
3.
4.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Oral Suspension should not be administered through feeding tubes due to its physical
1047
characteristics.
1048
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
1049
approximately 15 seconds and not to chew the microcapsules.
1050
1051
References:
1052
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
1053
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
1054
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
1055
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests-
1056
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
1057
PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
1058
Product’s Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from
1059
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
1060
Rockville, MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs
1061
for Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline,
1062
and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. 6.
1063
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
1064
Dis 1993; 167:1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for
1065
clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
1066
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
1067
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1068
1998;42(6):1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after
1069
prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology
1070
information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
1071
1072
Patient Information About:
1073
CIPRO®
1074
(ciprofloxacin hydrochloride) TABLETS
1075
CIPRO®
1076
(ciprofloxacin*) ORAL SUSPENSION
1077
This section contains important patient information about CIPRO (ciprofloxacin hydrochloride)
1078
Tablets and CIPRO (ciprofloxacin*) Oral Suspension and should be read completely before you begin
1079
treatment. This section does not take the place of discussion with your doctor or health care
1080
professional about your medical condition or your treatment. This section does not list all benefits and
1081
risks of CIPRO. If you have any concerns about your condition or your medicine, ask your doctor.
1082
Only your doctor can determine if CIPRO is right for you.
1083
What is CIPRO?
1084
CIPRO is an antibiotic used to treat bladder, kidney, prostate, cervix, stomach, intestine, lung, sinus,
1085
bone, and skin infections caused by certain germs called bacteria. CIPRO kills many types of bacteria
1086
that can infect these areas of the body. CIPRO has been shown in a large number of clinical trials to
1087
be safe and effective for the treatment of bacterial infections.
1088
Sometimes viruses rather than bacteria may infect the lungs and sinuses (for example the common
1089
cold). CIPRO, like all other antibiotics, does not kill viruses. You should contact your doctor if your
1090
condition is not improving while taking CIPRO.
1091
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Tablets are white to slightly yellow in color and are available in 100 mg, 250 mg, 500 mg and
1092
750 mg strengths. CIPRO Oral Suspension is white to slightly yellow in color and is available in
1093
concentrations of 250 mg per teaspoon (5%) and 500 mg per teaspoon (10%).
1094
How and when should I take CIPRO?
1095
CIPRO Tablets:
1096
Unless directed otherwise by your physician, CIPRO should be taken twice a day at approximately the
1097
same time, in the morning and in the evening. CIPRO can be taken with food or on an empty stomach.
1098
CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone;
1099
however, CIPRO may be taken with a meal that contains these products.
1100
You should take CIPRO for as long as your doctor prescribes it, even after you start to feel better.
1101
Stopping an antibiotic too early may result in failure to cure your infection. Do not take a double dose
1102
of CIPRO even if you miss a dose by mistake.
1103
CIPRO Oral Suspension:
1104
Take CIPRO Oral Suspension in the same way as above. In addition, remember to shake the bottle
1105
vigorously each time before use for approximately 15 seconds to make sure the suspension is
1106
mixed well. Be sure to swallow the required amount of suspension. Do not chew the microcapsules.
1107
Close the bottle completely after use. The product can be used for 14 days when stored in a
1108
refrigerator or at room temperature. After treatment has been completed, any remaining suspension
1109
should be discarded.
1110
Who should not take CIPRO?
1111
You should not take CIPRO if you have ever had a severe reaction to any of the group of antibiotics
1112
known as “quinolones”.
1113
CIPRO is not recommended during pregnancy or nursing, as the effects of CIPRO on the unborn child
1114
or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking CIPRO
1115
talk to your doctor before taking this medication.
1116
Due to possible side effects, CIPRO is not recommended for persons less than 18 years of age except
1117
for specific serious infections, such as complicated urinary tract infections.
1118
What are the possible side effects of CIPRO?
1119
CIPRO is generally well tolerated. The most common side effects, which are usually mild, include
1120
nausea, diarrhea, vomiting, and abdominal pain/discomfort. If diarrhea persists, call your health care
1121
professional.
1122
Rare cases of allergic reactions have been reported in patients receiving quinolones, including CIPRO,
1123
even after just one dose. If you develop hives, difficulty breathing, or other symptoms of a severe
1124
allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should stop
1125
taking CIPRO and call your health care professional.
1126
Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light
1127
such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet
1128
light while you are taking CIPRO.
1129
You should be careful about driving or operating machinery until you are sure CIPRO is not causing
1130
dizziness. Convulsions have been reported in patients receiving quinolone antibiotics including
1131
ciprofloxacin. Be sure to let your physician know if you have a history of convulsions. Quinolones,
1132
including ciprofloxacin, have been rarely associated with other central nervous system events
1133
including confusion, tremors, hallucinations, and depression.
1134
CIPRO has been rarely associated with inflammation of tendons. If you experience pain, swelling or
1135
rupture of a tendon, you should stop taking CIPRO and call your health care professional.
1136
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO has been associated with an increased rate of side effects with joints and surrounding
1137
structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their
1138
child’s physician if the child has a history of joint-related problems before taking this drug. Parents of
1139
pediatric patients should also notify their child’s physician of any joint related problems that occur
1140
during or following CIPRO therapy.
1141
If you notice any side effects not mentioned in this section, or if you have any concerns about side
1142
effects you may be experiencing, please inform your health care professional.
1143
What about other medications I am taking?
1144
CIPRO can affect how other medicines work. Tell your doctor about all other prescription and non-
1145
prescription medicines or supplements you are taking. This is especially important if you are taking
1146
theophylline. Other medications including warfarin, glyburide, and phenytoin may also interact with
1147
CIPRO.
1148
Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium,
1149
aluminum, iron or zinc can interfere with the absorption of CIPRO and may prevent it from working.
1150
Other medications such as sulcrafate and Videx® (didanosine) chewable/buffered tablets or pediatric
1151
powder may also stop CIPRO from working. You should take CIPRO either 2 hours before or 6 hours
1152
after taking these products.
1153
What if I have been prescribed CIPRO for possible anthrax exposure?
1154
CIPRO has been approved to reduce the chance of developing anthrax infection following exposure to
1155
the anthrax bacteria. In general, CIPRO is not recommended for children; however, it is approved for
1156
use in patients younger than 18 years old for anthrax exposure. If you are pregnant, or plan to become
1157
pregnant while taking CIPRO, you and your doctor should discuss if the benefits of taking CIPRO for
1158
anthrax outweigh the risks.
1159
CIPRO is generally well tolerated. Side effects that may occur during treatment to prevent anthrax
1160
might be acceptable due to the seriousness of the disease. You and your doctor should discuss the
1161
risks of not taking your medicine against the risks of experiencing side effects.
1162
CIPRO can cause dizziness, confusion, or other similar side effects in some people. Therefore, it is
1163
important to know how CIPRO affects you before driving a car or performing other activities that
1164
require you to be alert and coordinated such as operating machinery.
1165
Your doctor has prescribed CIPRO only for you. Do not give it to other people. Do not use it for a
1166
condition for which it was not prescribed. You should take your CIPRO for as long as your doctor
1167
prescribes it; stopping CIPRO too early may result in failure to prevent anthrax.
1168
Remember:
1169
Do not give CIPRO to anyone other than the person for whom it was prescribed.
1170
Take your dose of CIPRO in the morning and in the evening.
1171
Complete the course of CIPRO even if you are feeling better.
1172
Keep CIPRO and all medications out of reach of children.
1173
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
1174
1175
1176
1177
Bayer Pharmaceuticals Corporation
1178
400 Morgan Lane
1179
West Haven, CT 06516
1180
1181
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx Only
1182
1183
xxxxxxx
3/04
Bay o 9867
5202-2-A-U.S.-14
xxxxx
1184
©2004 Bayer Pharmaceuticals CorporationPrinted in U.S.A.
1185
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy.
1186
CIPRO (ciprofloxacin HCl) Tablets Made in U.S.A. and Germany
1187
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
XXXXXXXXX
3/25/04
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other
antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
DESCRIPTION
CIPRO® I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.) administration.
Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N)
hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V. solutions are available as sterile 1.0%
aqueous concentrates, which are intended for dilution prior to administration, and as 0.2% ready-for-use infusion
solutions in 5% Dextrose Injection. All formulas contain lactic acid as a solubilizing agent and hydrochloric acid for
pH adjustment. The pH range for the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2%
ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride. Solutions in
contact with the plastic container can leach out certain of its chemical components in very small amounts within the
expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has
been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue
culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean
maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the concentrations at 12 hours
were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (mg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously.
Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no
evidence of drug accumulation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by first pass
metabolism. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours has been shown
to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral
dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours
has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every
12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200
mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given
every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin
blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat,
muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are
generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of
the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which together
account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr. After
intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug.
Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL 0–2 hours after dosing and are
generally greater than 15 µg/mL 8–12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations
generally exceed 400 µg/mL 0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing.
The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours
after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous
dosing, only a small amount of the administered dose (<1%) is recovered from the bile as unchanged drug.
Approximately 15% of an I.V. dose is recovered from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin
indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
adults. Although the Cmax is increased 16–40%, the increase in mean AUC is approximately 30%, and can be at
least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%)
prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric
Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage adjustments
may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin
pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients with acute hepatic
insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7
years, the mean Cmax was 2.4 mg/L (range: 1.5 – 3.4 mg/L) and the mean AUC was 9.2 mg*h/L (range: 5.8 – 14.9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mg*h/L). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing
(10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 mg/L (range: 4.6 – 8.3 mg/L) in 10 children less than 1 year of age; and 7.2 mg/L
(range: 4.7 – 11.8 mg/L) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range:
11.8 – 32.0 mg*h/L) and 16.5 mg*h/L (range: 11.0 – 23.8 mg*h/L) in the respective age groups. These values are
within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of
pediatric patients with various infections, the predicted mean half-life in children is approximately 4 - 5 hours, and
the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin and
theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and
piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II
(DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and
recombination. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to
these classes of drugs may be susceptible to ciprofloxacin and other quinolones. There is no known cross-
resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops
slowly by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro.
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC)
by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in
clinical infections as described in the INDICATIONS AND USAGE section of the package insert for CIPRO I.V.
(ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a
surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX - ADDITIONAL
INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥90%)
strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin intravenous
formulations in treating clinical infections due to these microorganisms have not been established in adequate and
well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should
be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin
powder. The MIC values should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using
cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae
and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains
yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for
further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the
blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be
considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the
test should be repeated. This category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a
buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the
blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the
technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC
values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25
– 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25
– 1.0
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S. aureus
ATCC 29213
0.12
– 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized
procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks
impregnated with 5-mg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mg ciprofloxacin
disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar
supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains
yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference
laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of
the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms
that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg
ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test
Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous administration offers a
route of administration advantageous to the patient. Please see DOSAGE AND ADMINISTRATION for specific
recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia), Klebsiella
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus
epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus
parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute exacerbations
of chronic bronchitis.
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NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of presumed or
confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter
freundii, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis,
or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by Escherichia coli,
Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See CLINICAL
STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to
an increased incidence of adverse events compared to controls, including events related to joints and/or
surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL
STUDIES.) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes
in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to
aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication.4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify
organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with CIPRO I.V. may be
initiated before results of these tests are known; once results become available, appropriate therapy should be
continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during
treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide
information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of
bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other
antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to ciprofloxacin or any
member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND
LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing
Mothers subsections.)
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Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in
the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological
examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related
quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in
immature animals of various species. (See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous
system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal
thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones,
ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose
to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of
other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal
dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING
CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These
reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious
adverse events have been reported in patients receiving theophylline alone, the possibility that these reactions may
be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of
theophylline should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea,
urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions
require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen,
intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as
clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with
fatal outcome have also been reported extremely rarely in patients receiving ciprofloxacin along with other drugs.
The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be
discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea subsequent to the administration
of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia.
Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.
Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and
treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should
be avoided.
Tendon Rupture: Ruptures of the shoulder, hand, and Achilles and other tendon ruptures that required surgical
repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ciprofloxacin.
Post-marketing surveillance reports indicate that the risk may be increased in patients receiving concomitant
corticosteroids, especially in the elderly. Ciprofloxacin should be discontinued if the patient experiences pain,
inflammation, or rupture of a tendon.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW INFUSION OVER A
PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the intravenous administration of
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ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small veins of the hand
are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS,
Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine
of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to
ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine
should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of
highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal function.
(See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been
observed in some patients who were exposed to direct sunlight while receiving some members of the quinolone
class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant
bacteria.
Information For Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO IV should only be used to treat bacterial infections. They do not treat viral
infections (e.g., the common cold). When CIPRO IV is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be taken exactly
as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the
immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable
by CIPRO IV or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to
discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to
this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or
coordination.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of caffeine
accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience pain,
inflammation, or rupture of a tendon.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to notify their
physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding
tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their child’s
physician if the child has a history of joint-related problems before taking this drug. Parents of pediatric patients
should also notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin
therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may
lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in
increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided,
serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This
may lead to reduced clearance of caffeine and prolongation of its serum half-life.
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Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in
patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant
ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients, resulted in
severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given
concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or
its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation
tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of
ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially
leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic
reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant
ciprofloxacin therapy is indicated.
Metoclopramide accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma
concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Animal studies have shown that the combination of very high doses of quinolones and certain non-steroidal anti-
inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V. piperacillin
sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2 hour and 1.18 µg/mL
between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been conducted
with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to
ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7-
and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of
UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5
hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time
to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin
(mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34
weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from
16–32 weeks in mice treated concomitantly with UVA and other quinolones.3
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In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from
similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans
is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the
highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies in
pregnant women. An expert review of published data on experiences with ciprofloxacin use during pregnancy by
TERIS – the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there
is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to
ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluoroquinolones during
embryogenesis was not associated with increased risk of major malformations. The reported rates of major
congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background
incidence of major malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not
differ between the groups and there were no clinically significant musculoskelatal dysfunctions up to one year of
age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester
exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among
live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence
ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse
reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to
ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies, of which most
experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects
or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their
developing fetuses. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the
potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times
the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of
harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately
0.4- and 1.3-times the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal
toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed
at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing
infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking
ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing
joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment
indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric
dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to
Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to the controls, including those related to
joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract
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infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control
agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and
9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41%
(138/335) in the ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS
and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-
blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67
patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose
q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose
q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not
studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0-
93 days). This study was not designed to determine long term effects and the safety of repeated exposure to
ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the
ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients
in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and
frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten
day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without
other abnormalities eight months after treatment. However, the relationship of this event to the patient’s course of
ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age and 10%
were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of
adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for
patients greater than 65 years of age with normal renal function. However, since some older individuals experience
reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients,
and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral ciprofloxacin, 49,038
patients received courses of the drug. Most of the adverse events reported were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued
because of an adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy
durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests
abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1% of patients
treated with intravenous ciprofloxacin : nausea, diarrhea, central nervous system disturbance, local I.V. site
reactions, liver function tests abnormal eosinophilia, headache, restlessness, and rash. Many of these events were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no
treatment. Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These may appear
as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous
administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration, that occurred in
1% or less of ciprofloxacin patients are listed below:
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BODY AS A WHOLE:
abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia,
tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina pectoris,
atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression, dysphasia, phobia,
depersonalization, manic reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness,
paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal
gait, grand mal convulsion, anorexia
GASTROINTESTINAL:
ileus,
jaundice,
gastrointestinal
bleeding,
C.
difficile
associated
diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric pain,
constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence, hepatitis, painful oral
mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain, achiness, flare up of
gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal calculi, frequent
urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia, candiduria, vaginitis, breast pain.
Crystalluria, cylindruria, hematuria and albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema, respiratory
distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions, erythema multiforme/Stevens-Johnson
syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck,
conjunctivae, hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change in color
perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, chromatopsia, a
bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to
elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V. P.O. sequential) with
intravenous beta-lactam control antibiotics, the CNS adverse event profile of ciprofloxacin was comparable to that of
the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was compared to a
cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to
17 years of age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa
Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment
was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and
neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well
as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were
evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint
exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of
motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 %
(21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30
days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they
received I.V. or oral therapy. Ciprofloxacin-treated patients were more likely to report more than one event and on
more than one occasion compared to control patients. These events occurred in all age groups and the rates were
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consistently higher in the ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these
events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed
4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports
activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months
without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control
group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be
concluded that the ciprofloxacin group had findings comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and
somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6
weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the
comparator group. The most frequent events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared
to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated
patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse events were
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other
adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal
pain 3.3%, accidental injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in
adults during clinical trials or post-marketing experience may also occur in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide marketing
experience with quinolones, including ciprofloxacin. Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of
the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal
connection to the drug.
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Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence,
glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic necrosis, hyperesthesia, hypertonia,
hypesthesia, hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia,
monoliasis (oral, gastrointestinal, vaginal) myalgia, myasthenia, myasthenia gravis (possible exacerbation),
myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), phenytoin alteration (serum),
potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal
calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, toxic
epidermal necrolysis, triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See
PRECAUTIONS.)
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with intravenous
ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
—
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin;
Hematologic
—
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit;
Renal
—
elevations of serum creatinine, BUN, and uric acid;
Other
—
elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides.
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte count,
immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ GT), decreased
BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum potassium,
elevated serum potassium, elevated serum cholesterol. Other changes occurring rarely during administration of
ciprofloxacin were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated
sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding
diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive treatment.
Adequate hydration must be maintained. Only a small amount of ciprofloxacin (<10%) is removed from the body
after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous
doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at dosages
described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein will minimize patient
discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and nature of the
infection, the susceptibility of the causative microorganism, the integrity of the patient’s host-defense mechanisms,
and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
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Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
* used in conjunction with metronidazole. (See product labeling for prescribing information.)
† DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This indication is
based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to
predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations,
see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION. Total duration of ciprofloxacin administration
(I.V. or oral) for inhalational anthrax (post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral administration
are available. Parenteral therapy may be switched to oral CIPRO when the condition warrants, at the discretion of
the physician. (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion; however, the drug
is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These
alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended for patients with severe renal dysfunction.
The following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine
clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
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Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic insufficiency, careful
monitoring is suggested.
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DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered orally as described in the Dosage Guidelines table. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or pyelonephritis should be
determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection
were initiated on 6 to 10 mg/kg I.V. every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12
hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 8 hours
Complicated
Urinary Tract or
Pyelonephritis
(patients from 1
to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 12
hours
10-21
days*
Intravenous
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)**
Oral
15 mg/kg
(maximum 500 mg per dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was
determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis
spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human
populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated
urinary tract infection and pyelonephritis. No information is available on dosing adjustments necessary for pediatric
patients with moderate to severe renal insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The intravenous dose
should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO I.V. This should be diluted
with a suitable intravenous solution to a final concentration of 1–2mg/mL. (See COMPATIBILITY AND STABILITY.)
The resulting solution should be infused over a period of 60 minutes by direct infusion or through a Y-type
intravenous infusion set which may already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily the
administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of CIPRO I.V. and
another drug is necessary each drug should be given separately in accordance with the recommended dosage and
route of administration for each drug.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in flexible containers
of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted and may be infused as
described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to concentrations of 0.5
to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is available in
200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed solution is supplied in latex-
free flexible containers as follows:
VIAL:
manufactured by Bayer Corporation and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Abbott Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Baxter Healthcare Corporation, Deerfield, IL
60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
STORAGE
Vial:
Store between 5 – 30°C (41 – 86°F).
Flexible Container:
Store between 5 – 25°C (41 – 77°F).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species
tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young
beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint.
At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin
doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon
comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by
histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with
arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from
the joint reduced the lesions but did not totally prevent them.
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Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which
predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus
monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-
times the highest recommended therapeutic dose based upon mg/m2). After 6 months of intravenous dosing at 10
mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20
mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon
mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release because they are partially
antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces
hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone and
indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in
the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving
oral and intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin pharmacokinetics have
been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in
human adults receiving 500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously
every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In a
study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3
µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute intravenous infusions of
10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally
every 12 hours achieve a mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data,
including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this
indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105)
spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin
for the anthrax strain used in this study was 0.08 µg/mL. In the animals studied, mean serum concentrations of
ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to
1.69 µg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5.
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-
exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-
treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q
4h, for the empirical therapy of febrile neutropenic patients were studied in one large pivotal multicenter,
randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
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Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological
eradication of infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of
infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to
an increased incidence of adverse events compared to controls, including events related to joints and/or
surrounding tissues.
Ciprofloxacin, administered I.V. and /or orally, was compared to a cephalosporin for treatment of complicated
urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years).
The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The
primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new
infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a
causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature
discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between
ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic
Eradication
of
the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new
infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2,
NCCLS, Wayne, PA, January, 2000. 2. National Committee for Clinical Laboratory Standards, Performance
Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-
A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and
Dermatological Drug Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD
20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in
rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6. Friedlander AM, et al. Postexposure prophylaxis against
experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of
drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a
multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339. 9. Schaefer C,
Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry
of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:
83-89.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516 USA
Rx Only
XXXXXXX 3/04
BAY q 3939
5202-4-A-U.S.-9
©2004 Bayer Pharmaceuticals Corporation
xxxxx
Printed In U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:06.691629
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19537s049,19857s031,19847se5-027,20780se5-013_cipro_lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
11,771
|
CIPRO®
(ciprofloxacin hydrochloride)
TABLETS
CIPRO®
(ciprofloxacin*)
ORAL SUSPENSION
XXXXXX
11/05
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO®
Tablets and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by bacteria.
DESCRIPTION
CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light
yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is
C17H18FN3O3•HCl•H2O and its chemical structure is as follows:
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light
yellow crystalline substance and its chemical structure is as follows:
CIPRO film-coated tablets are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent)
strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are cornstarch,
microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, hypromellose,
titanium dioxide, and polyethylene glycol.
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish
suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of
ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See instructions for
USE/HANDLING). The components of the suspension have the following compositions:
Microcapsules - ciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20.
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
* Does not comply with USP with regard to “loss on drying” and “residue on ignition”.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal
tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss
by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are
shown in the chart for the 250 mg to 1000 mg dose range.
Dose
(mg)
Maximum
Serum Concentration
(µg/mL)
Area
Under Curve (AUC)
(µg•hr/mL)
250
1.2
4.8
500
2.4
11.6
750
4.3
20.2
1000
5.4
30.8
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimi-
nation half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations
increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been
shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400
mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed
with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that
produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
Steady-state Pharmacokinetic Parameters
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
AUC (µg•hr/mL)
q12h, P.O.
13.7a
q12h, I.V.
12.7a
q12h, P.O.
31.6b
q8h, I.V.
32.9c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
aAUC 0-12h
bAUC 24h=AUC0-12h x 2
cAUC 24h=AUC0-8h x 3
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high
enough to cause significant protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations
often exceed serum concentrations in both men and women, particularly in genital tissue including the
prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of
the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the
cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism: Four metabolites have been identified in human urine which together account for approxi-
mately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than
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For current labeling information, please visit https://www.fda.gov/drugsatfda
unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2
(CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily
metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could
lead to clinically significant adverse events of the coadministered drug (see
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL during
the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion
of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin,
which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120
mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately
20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from
either biliary clearance or transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in the
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather
than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The
overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The
pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Concurrent
administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the
bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS).
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other
adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See WARNINGS: PRECAUTIONS.)
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the
increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These
differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
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adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
acute hepatic insufficiency, however, have not been fully elucidated.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following
microorganisms, both in vitro and in clinical infections as described in the INDICATIONS
AND USAGE section of the package insert for CIPRO (ciprofloxacin hydrochloride) Tablets
and CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Campylobacter jejuni
Proteus mirabilis
Citrobacter diversus
Proteus vulgaris
Citrobacter freundii
Providencia rettgeri
Enterobacter cloacae
Providencia stuartii
Escherichia coli
Pseudomonas aeruginosa
Haemophilus influenzae
Salmonella typhi
Haemophilus parainfluenzae
Serratia marcescens
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Klebsiella pneumoniae
Shigella boydii
Moraxella catarrhalis
Shigella dysenteriae
Morganella morganii
Shigella flexneri
Neisseria gonorrhoeae
Shigella sonnei
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains only)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Pasteurella multocida
Aeromonas hydrophila
Salmonella enteritidis
Edwardsiella tarda
Vibrio cholerae
Enterobacter aerogenes
Vibrio parahaemolyticus
Klebsiella oxytoca
Vibrio vulnificus
Legionella pneumophila
Yersinia enterocolitica
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus
parainfluenzae, and Neisseria gonorrhoeaea:
MIC (µg/mL)
Interpretation
≤1
Susceptible
(S)
2
Intermediate (I)
≥4
Resistant
(R)
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
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For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
MIC (µg/mL)
Interpretation
≤1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
MIC (µg/mL)
Interpretation
≤ 0.06
Susceptible
(S)
0.12 – 0.5
Intermediate (I)
≥1
Resistant
(R)
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
growth supplement.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
N. gonorrhoeaeb
ATCC 49226
0.001 – 0.008
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
bThis quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution
procedure using GC agar base and 1% defined growth supplement.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus
parainfluenzae, and Neisseria gonorrhoeaea:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 – 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using
Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
Zone Diameter (mm)
Interpretation
≥ 41
Susceptible
(S)
28 – 40
Intermediate (I)
≤ 27
Resistant
(R)
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined
growth supplement.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30 – 40
H. influenzaea
ATCC 49247
34 – 42
N. gonorrhoeaeb
ATCC 49226
48 – 58
P. aeruginosa
ATCC 27853
25 – 33
S. aureus
ATCC 25923
22 – 30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226
performed by disk diffusion using GC agar base and 1% defined growth supplement.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus
epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
saprophyticus.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the
treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
morganii,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
Staphylococcus
aureus
(methicillin-susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
Shigella boydii †, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial
therapy is indicated.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been
demonstrated.
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
significant outcome, efficacy was studied in fewer than 10 patients.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in
order to isolate and identify organisms causing infection and to determine their susceptibility to
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
results become available appropriate therapy should be continued. As with other drugs, some strains of
Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin.
Culture and susceptibility testing performed periodically during therapy will provide information not
only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial
resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by susceptible bacteria. When culture and susceptibility information are available, they should
be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS, Drug
Interactions.)
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
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Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus,
and respiratory failure. Although similar serious adverse effects have been reported in patients
receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin
cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be
administered as indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and
hepatic necrosis with fatal outcome have also been rarely reported in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to
ciprofloxacin cannot be excluded. Ciprofloxacin should be discontinued at the first appearance
of a skin rash or any other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly
all antibacterial agents, including ciprofloxacin, and may range in severity from mild to
life-threatening. Therefore, it is important to consider this diagnosis in patients who
present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit
overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one
primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures
should be initiated. Mild cases of pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases, consideration should be given to
management with fluids and electrolytes, protein supplementation, and treatment with an
antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis
should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
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weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in
patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be
discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest
and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after
three months.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in patients who are exposed to direct sunlight while receiving some members of the
quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if
phototoxicity occurs.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Information for Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be
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taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
other antibacterial drugs in the future.
• that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered
drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may
be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken
with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of
ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that
contains these products.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to
discontinue therapy if phototoxicity occurs.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience
pain, inflammation, or rupture of a tendon.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increase the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
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Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc
may substantially decrease its absorption, resulting in serum and urine levels considerably lower than
desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents
with ciprofloxacin.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions,
resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in
the level of ciprofloxacin in the serum. This should be considered if patients are receiving both
drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might
increase the risk of methotrexate associated toxic reactions. Therefore, patients under
methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is
indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to
reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin, and the test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
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Dominant Lethal Test (Mice)
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Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maxi-
mum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
weeks in mice treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance
of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and
well-controlled studies in pregnant women. An expert review of published data on experiences with
ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that
therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and
quality of data=fair), but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones
(52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero
exposure to fluoroquinolones during embryogenesis was not associated with increased risk of
major malformations. The reported rates of major congenital malformations were 2.2% for the
fluoroquinolone group and 2.6% for the control group (background incidence of major
malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not
differ between the groups and there were no clinically significant musculoskeletal dysfunctions up
to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during
pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
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Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and
100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based
upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended
therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing
joints
of
juvenile
animals
resulting
in
lameness.
(See
ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including events related to joints and/or surrounding tissues. The
rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless
of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age
were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
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patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin
encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65
years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled
out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
reactions may be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function. However, since some
older individuals experience reduced renal function by virtue of their advanced age, care should be taken
in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.0% of
orally treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients
are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in
extremities, injection site reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis,
phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression,
paresthesia, abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
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METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain,
flare up of gout
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary
retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
hemoptysis, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity,
flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands,
cutaneous candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception,
overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad
taste, chromatopsia
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be
related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
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An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment.
An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of
overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin
cannot be excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening
anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic
necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow
depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus,
pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin
alteration (serum), potassium elevation (serum), prothrombin time prolongation or decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like
reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes,
toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also
INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION.)
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
regard to drug relationship are listed below:
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
(0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%),
elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
observed and given supportive treatment, including monitoring of renal function and administration of
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
is removed from the body after hemodialysis or peritoneal dialysis.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats,
and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral
doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs
observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed
in these animals, occurring 10-14 days after dosing.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the Dosage
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Guidelines table.
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s
host-defense mechanisms, and the status of renal function and hepatic function.
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
however, for severe and complicated infections more prolonged therapy may be required.
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
solution, other highly buffered drugs, or other products containing calcium, iron or zinc.
ADULT DOSAGE GUIDELINES
Infection
Severity
Dose
Frequency Usual Durations†
Urinary Tract
Acute Uncomplicated
250 mg
q 12 h
3 Days
Mild/Moderate
250 mg
q 12 h
7 to 14 Days
Severe/Complicated
500 mg
q 12 h
7 to 14 Days
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 Days
Prostatitis
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 Days
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 Days
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 Days
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 Days
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 Days
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
Gonococcal Infections
Inhalational anthrax
500 mg
q 12 h
60 Days
(post-exposure)**
* used in conjunction with metronidazole
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have
disappeared, except for inhalational anthrax (post-exposure).
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely
to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens).
Equivalent AUC Dosing Regimens
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended, particularly for patients with severe renal dysfunction. The following table provides
dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dose
> 50
See Usual Dosage.
30 – 50
250 – 500 mg q 12 h
5 – 29
250 – 500 mg q 18 h
Patients on hemodialysis
250 – 500 mg q 24 h (after dialysis)
or Peritoneal dialysis
When only the serum creatinine concentration is known, the following formula may be used to estimate
creatinine clearance.
Men: Creatinine clearance (mL/min) =
Weight (kg) x (140 - age)
72 x serum creatinine (mg/dL)
Women: 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered
at the intervals noted above. Patients should be carefully monitored.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
Guidelines table. An increased incidence of adverse events compared to controls, including
events related to joints and/or surrounding tissues, has been observed. (See ADVERSE
REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
HOW SUPPLIED
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
tablets containing 250 mg ciprofloxacin. The 250 mg tablet is coded with the word “CIPRO” on one side
and “250” on the reverse side. CIPRO is also available as capsule shaped, slightly yellowish film-coated
tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet is coded with the word “CIPRO”
on one side and “500” on the reverse side. The 750 mg tablet is coded with the word “CIPRO” on one
side and “750” on the reverse side. CIPRO 250 mg, 500 mg, and 750 mg are available in bottles of 50,
100, and Unit Dose packages of 100.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Strength
NDC Code
Tablet Identification
Bottles of 50:
750 mg
NDC 0085-1756-01
CIPRO 750
Bottles of 100:
250 mg
NDC 0085-1758-01
CIPRO 250
500 mg
NDC 0085-1754-01
CIPRO 500
Unit Dose
Package of 100:
250 mg
NDC 0085-1758-02
CIPRO 250
500 mg
NDC 0085-1754-02
CIPRO 500
750 mg
NDC 0085-1756-02
CIPRO 750
Store below 30°C (86°F).
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
pharmacist. See Instructions To The Pharmacist For Use/Handling.
Total volume
Ciprofloxacin
Ciprofloxacin
Strengths after reconstitution
Concentration
contents per bottle
NDC Code
5%
100 mL
250 mg/5 mL
5,000 mg
0085-1777-01
10%
100 mL
500 mg/5 mL
10,000 mg
0085-1773-01
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
teaspoon is provided for the patient.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in
juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal.
In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by
histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times
the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This
dose was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release, since they are
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
produces hypotension but the effect in this species is inconsistent and less pronounced.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days
Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by
Patient at 5 to 9 Days
Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new
infections.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day drug administration period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
which must be combined prior to dispensing.
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of ciprofloxacin.
Appropriate Dosing Volumes of the Oral Suspensions:
Dose
5%
10%
250 mg
5 mL
2.5 mL
500 mg
10 mL
5 mL
750 mg
15 mL
7.5 mL
Preparation of the suspension:
1. The small bottle
contains the
microcapsules, the
large bottle
contains the
diluent.
3. Pour the
microcapsules
completely into the
larger bottle of
diluent. Do not add
water to the
suspension.
3.
2.
1.
4.
2. Open both bottles.
Child-proof cap: Press
down according to
instructions on the cap
while turning to the
left.
4. Remove the top layer
of the diluent bottle
label (to reveal the
CIPRO Oral
Suspension label).
Close the large bottle
completely according
to the directions on the
cap and shake
vigorously for about
15 seconds. The
suspension is ready for
use.
CIPRO Oral Suspension should not be administered through feeding tubes due to its
physical characteristics.
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
approximately 15 seconds and not to chew the microcapsules.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National
Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk
Susceptibility Tests-Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective
Drug and Dermatological Drug Product’s Advisory Committee meeting, March 31, 1993,
Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff,
HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. 4. 21 CFR 314.510
(Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses). 5. Kelly DJ,
et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. 6. Friedlander AM, et al.
Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993;
167:1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians
(TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8. Loebstein R,
Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a
multicenter
prospective
controlled
study.
Antimicrob
Agents
Chemother.
1998;42(6):1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome
after prenatal quinolone exposure. Evaluation of a case registry of the European network of
teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
Patient Information About:
CIPRO®
(ciprofloxacin hydrochloride) TABLETS
CIPRO®
(ciprofloxacin*) ORAL SUSPENSION
This section contains important patient information about CIPRO (ciprofloxacin hydrochloride)
Tablets and CIPRO (ciprofloxacin*) Oral Suspension and should be read completely before you begin
treatment. This section does not take the place of discussion with your doctor or health care
professional about your medical condition or your treatment. This section does not list all benefits and
risks of CIPRO. If you have any concerns about your condition or your medicine, ask your doctor. Only
your doctor can determine if CIPRO is right for you.
What is CIPRO?
CIPRO is an antibiotic used to treat bladder, kidney, prostate, cervix, stomach, intestine, lung, sinus,
bone, and skin infections caused by certain germs called bacteria. CIPRO kills many types of bacteria
that can infect these areas of the body. CIPRO has been shown in a large number of clinical trials to be
safe and effective for the treatment of bacterial infections.
Sometimes viruses rather than bacteria may infect the lungs and sinuses (for example the common
cold). CIPRO, like all other antibiotics, does not kill viruses. You should contact your doctor if your
condition is not improving while taking CIPRO.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Tablets are white to slightly yellow in color and are available in 250 mg, 500 mg and 750 mg
strengths. CIPRO Oral Suspension is white to slightly yellow in color and is available in concentrations
of 250 mg per teaspoon (5%) and 500 mg per teaspoon (10%).
How and when should I take CIPRO?
CIPRO Tablets:
Unless directed otherwise by your physician, CIPRO should be taken twice a day at approximately the
same time, in the morning and in the evening. CIPRO can be taken with food or on an empty stomach.
CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone;
however, CIPRO may be taken with a meal that contains these products.
You should take CIPRO for as long as your doctor prescribes it, even after you start to feel better.
Stopping an antibiotic too early may result in failure to cure your infection. Do not take a double dose
of CIPRO even if you miss a dose by mistake.
CIPRO Oral Suspension:
Take CIPRO Oral Suspension in the same way as above. In addition, remember to shake the bottle vig-
orously each time before use for approximately 15 seconds to make sure the suspension is mixed well.
Be sure to swallow the required amount of suspension. Do not chew the microcapsules. Close the
bottle completely after use. The product can be used for 14 days when stored in a refrigerator or at
room temperature. After treatment has been completed, any remaining suspension should be discarded.
Who should not take CIPRO?
You should not take CIPRO if you have ever had a severe reaction to any of the group of antibiotics
known as “quinolones”. You should also not take CIPRO if you are also taking a medication called
tizanidine (Zanaflex® ), as excessive side effects from tizanidine are likely to occur.
CIPRO is not recommended during pregnancy or nursing, as the effects of CIPRO on the unborn child
or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking CIPRO
talk to your doctor before taking this medication.
Due to possible side effects, CIPRO is not recommended for persons less than 18 years of age
except for specific serious infections, such as complicated urinary tract infections.
What are the possible side effects of CIPRO?
CIPRO is generally well tolerated. The most common side effects, which are usually mild, include
nausea, diarrhea, vomiting, and abdominal pain/discomfort. If diarrhea persists, call your health care
professional.
Rare cases of allergic reactions have been reported in patients receiving quinolones, including CIPRO,
even after just one dose. If you develop hives, difficulty breathing, or other symptoms of a severe
allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should stop
taking CIPRO and call your health care professional.
Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light
such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet light
while you are taking CIPRO.
You should be careful about driving or operating machinery until you are sure CIPRO is not causing
dizziness. Convulsions have been reported in patients receiving quinolone antibiotics including
ciprofloxacin. Be sure to let your physician know if you have a history of convulsions. Quinolones,
including ciprofloxacin, have been rarely associated with other central nervous system events
including confusion, tremors, hallucinations, and depression.
CIPRO has been rarely associated with inflammation of tendons. If you experience pain, swelling or
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rupture of a tendon, you should stop taking CIPRO and call your health care professional.
CIPRO has been associated with an increased rate of side effects with joints and surrounding
structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform
their child’s physician if the child has a history of joint-related problems before taking this drug.
Parents of pediatric patients should also notify their child’s physician of any joint related
problems that occur during or following CIPRO therapy.
If you notice any side effects not mentioned in this section, or if you have any concerns about side
effects you may be experiencing, please inform your health care professional.
What about other medications I am taking?
CIPRO can affect how other medicines work. Tell your doctor about all other prescription and
non-prescription medicines or supplements you are taking. This is especially important if you are
taking tizanidine (Zanaflex® ) or theophylline. You should not take Cipro if you are also taking
tizanidine. Other medications including warfarin, glyburide, and phenytoin may also interact with
CIPRO.
Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium,
aluminum, iron or zinc can interfere with the absorption of CIPRO and may prevent it from working.
Other medications such as sulcrafate and Videx® (didanosine) chewable/buffered tablets or pediatric
powder may also stop CIPRO from working. You should take CIPRO either 2 hours before or 6 hours
after taking these products.
What if I have been prescribed CIPRO for possible anthrax exposure?
CIPRO has been approved to reduce the chance of developing anthrax infection following exposure to
the anthrax bacteria. In general, CIPRO is not recommended for children; however, it is approved for
use in patients younger than 18 years old for anthrax exposure. If you are pregnant, or plan to become
pregnant while taking CIPRO, you and your doctor should discuss if the benefits of taking CIPRO for
anthrax outweigh the risks.
CIPRO is generally well tolerated. Side effects that may occur during treatment to prevent anthrax
might be acceptable due to the seriousness of the disease. You and your doctor should discuss the risks
of not taking your medicine against the risks of experiencing side effects.
CIPRO can cause dizziness, confusion, or other similar side effects in some people. Therefore, it is
important to know how CIPRO affects you before driving a car or performing other activities that
require you to be alert and coordinated such as operating machinery.
Your doctor has prescribed CIPRO only for you. Do not give it to other people. Do not use it for a
condition for which it was not prescribed. You should take your CIPRO for as long as your doctor
prescribes it; stopping CIPRO too early may result in failure to prevent anthrax.
Remember:
Do not give CIPRO to anyone other than the person for whom it was prescribed.
Take your dose of CIPRO in the morning and in the evening.
Complete the course of CIPRO even if you are feeling better.
Keep CIPRO and all medications out of reach of children.
* Does not comply with USP with regard to “loss on drying” and “residue on ignition”.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Distributed by:
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
Corporation.
Rx Only
XXXXXXX
9/05
Bay o 9867
5202-2-A-U.S.-19
XXX
©2005 Bayer Pharmaceuticals Corporation
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy.
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
This label may not be the latest approved by FDA.
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
XXXXXXXXX
11/05
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
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The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg
administered intravenously. Comparison of the pharmacokinetic parameters following the 1st
and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no
substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin
given over 60 minutes every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every
12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8
hours has been shown to produce an AUC at steady-state equivalent to that produced by a
750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that
observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours
produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial
secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It
has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug
diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak
serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are
lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human
urine which together account for approximately 10% of the intravenous dose. The binding of
ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin
with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations
of these drugs and could lead to clinically significant adverse events of the coadministered drug
(see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35
L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in
the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually
exceed 200 µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours
after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL
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0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The
renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually
complete by 24 hours after dosing.
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Although bile concentrations of ciprofloxacin are several fold higher than serum
concentrations after intravenous dosing, only a small amount of the administered dose (< 1%)
is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered
from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in
patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
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tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
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Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
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a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with
a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
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Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or
Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for
the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus
(methicillin susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
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If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy
with CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
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reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin
cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to
life-threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In
moderate to severe cases, consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically effective against C.
difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
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order to prevent the development of an irreversible condition.
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Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased
in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be
discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest
and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of the
quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or
not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
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• that ciprofloxacin increase the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility
of caffeine accumulation when products containing caffeine are consumed while taking
ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience
pain, inflammation, or rupture of a tendon.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments
made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
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risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems
gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but
the data are insufficient to state that there is no risk.7
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A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg
(0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively)
and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral
ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest
recommended therapeutic dose based upon mg/m2) produced gastrointestinal toxicity resulting
in maternal weight loss and an increased incidence of abortion, but no teratogenicity was
observed at either dose level. After intravenous administration of doses up to 20 mg/kg
(approximately 0.3-times the highest recommended therapeutic dose based upon mg/m2) no
maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See
WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure),
see DOSAGE
AND
ADMINISTRATION
and INHALATIONAL
ANTHRAX
–
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
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pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including those related to joints and/or surrounding tissues. The rates
of these events in pediatric patients with complicated urinary tract infection and pyelonephritis
within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents.
The rates of these events occurring at any time up to the one year follow-up were 13.7%
(46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug
relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of
age were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney,
and the risk of adverse reactions may be greater in patients with impaired renal function. No
alteration of dosage is necessary for patients greater than 65 years of age with normal renal
function. However, since some older individuals experience reduced renal function by virtue of
their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
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Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported
were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V.
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as
local skin reactions which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
hypertension,
hypotension,
angina
pectoris,
atrial
flutter,
ventricular
ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions
including
life-threatening anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative
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dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae,
hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning,
paresthesia, erythema, swelling, photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these
events are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions
to include these events in labeling are typically based on one or more of the following factors:
(1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection
to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative
dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
failure, hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural),
jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis (oral,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible exacerbation),
myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome),
peripheral neuropathy, phenytoin alteration (serum), potassium elevation (serum), prothrombin
time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous
colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal
calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon
rupture, torsade de pointes, toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride
elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also
INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a
larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation
of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax (post-exposure) is
60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table
below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the
liver and through the intestine. These alternative pathways of drug elimination appear to
compensate for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended for patients with severe renal dysfunction. The
following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased
incidence of adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of
1–2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: manufactured for Bayer Pharmaceuticals Corporation by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Hospira, Inc.,
Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean
peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects
on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
provide the basis for this indication.4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In
the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean
steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5.
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin
beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group
(9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the
30-day drug administration period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA,
January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville,
MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for
Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and
ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis
1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians
(TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8. Loebstein R, Addis
A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter
prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339. 9. Schaefer C,
Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a
case registry of the European network of teratology information services (ENTIS). Eur J Obstet
Gynecol Reprod Biol. 1996;69:83-89.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for:
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Distributed by:
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
Corporation.
Rx Only
XXXX
11/05
©2005 Bayer Pharmaceuticals Corporation
XXXXX
XXXX
BAY q 3939
5202-4-A-U.S.-15
Printed In U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO® XR
(ciprofloxacin* extended-release tablets)
XXXXXX
11/05
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® XR and
other antibacterial drugs, CIPRO XR should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO XR (ciprofloxacin* extended-release tablets) contains ciprofloxacin, a synthetic broad-spectrum
antimicrobial agent for oral administration. CIPRO XR tablets are coated, bilayer tablets consisting of an
immediate-release layer and an erosion-matrix type controlled-release layer. The tablets contain a
combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride and ciprofloxacin
betaine
(base).
Ciprofloxacin
hydrochloride
is
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-
(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. It is provided as a mixture of the monohydrate and
the sesquihydrate. The empirical formula of the monohydrate is C17H18FN3O3 • HCl • H2O and its molecular
weight is 385.8. The empirical formula of the sesquihydrate is C17H18FN3O3 • HCl • 1.5 H2O and its
molecular weight is 394.8. The drug substance is a faintly yellowish to light yellow crystalline substance. The
chemical structure of the monohydrate is as follows:
Ciprofloxacin betaine is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid. As a hydrate, its empirical formula is C17H18FN3O3 • 3.5 H2O and its molecular weight is 394.3. It is a
pale yellowish to light yellow crystalline substance and its chemical structure is as follows:
CIPRO XR is available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strengths. CIPRO XR
tablets are nearly white to slightly yellowish, film-coated, oblong-shaped tablets. Each CIPRO XR 500
mg tablet contains 500 mg of ciprofloxacin as ciprofloxacin HCl (287.5 mg, calculated as ciprofloxacin
on the dried basis) and ciprofloxacin† (212.6 mg, calculated on the dried basis). Each CIPRO XR 1000
mg tablet contains 1000 mg of ciprofloxacin as ciprofloxacin HCl (574.9 mg, calculated as ciprofloxacin
on the dried basis) and ciprofloxacin† (425.2 mg, calculated on the dried basis). The inactive ingredients
are crospovidone, hypromellose, magnesium stearate, polyethylene glycol, silica colloidal anhydrous,
succinic acid, and titanium dioxide.
* as ciprofloxacin† and ciprofloxacin hydrochloride
† does not comply with the loss on drying test and residue on ignition test of the USP monograph.
CLINICAL PHARMACOLOGY
Absorption
CIPRO XR tablets are formulated to release drug at a slower rate compared to immediate-release tablets.
Approximately 35% of the dose is contained within an immediate-release component, while the remain-
ing 65% is contained in a slow-release matrix.
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Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with
CIPRO XR. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release BID treatment,
the Cmax of CIPRO XR 500 mg and 1000 mg once daily are higher than the corresponding BID doses,
while the AUCs over 24 hours are equivalent.
The following table compares the pharmacokinetic parameters obtained at steady state for these four
treatment regimens (500 mg QD CIPRO XR versus 250 mg BID ciprofloxacin immediate-release
tablets and 1000 mg QD CIPRO XR versus 500 mg BID ciprofloxacin immediate-release).
Ciprofloxacin Pharmacokinetics (Mean ± SD) Following CIPRO® and CIPRO XR Administration
Cmax
(mg/L)
AUC0-24h
(mg•h/L)
T1/2 (hr)
Tmax (hr) §
CIPRO XR 500 mg QD
1.59 ± 0.43
7.97 ± 1.87
6.6 ± 1.4
1.5 (1.0 – 2.5)
CIPRO 250 mg BID
1.14 ± 0.23
8.25 ± 2.15
4.8 ± 0.6
1.0 (0.5 – 2.5)
CIPRO XR 1000 mg QD
3.11 ± 1.08
16.83 ± 5.65
6.31 ± 0.72
2.0 (1 – 4)
CIPRO 500 mg BID
2.06 ± 0.41
17.04 ± 4.79
5.66 ± 0.89
2.0 (0.5 – 3.5)
§ median (range)
Results of the pharmacokinetic studies demonstrate that CIPRO XR may be administered with or
without food (e.g. high-fat and low-fat meals or under fasted conditions).
Distribution
The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1 – 2.7 L/kg.
Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of
ciprofloxacin into a variety of tissues. The binding of ciprofloxacin to serum proteins is 20% to 40%,
which is not likely to be high enough to cause significant protein binding interactions with other drugs.
Following administration of a single dose of CIPRO XR, ciprofloxacin concentrations in urine
collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets;
in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for
the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.
Metabolism
Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial
activity, but are less active than unchanged ciprofloxacin. The primary metabolites are
oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total
dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (M4). The
relative proportion of drug and metabolite in serum corresponds to the composition found in urine.
Excretion of these metabolites was essentially complete by 24 hours after dosing. Ciprofloxacin is an
inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration
of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased
plasma concentrations of these drugs and could lead to clinically significant adverse events of
the coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS:
Drug Interactions).
Elimination
The elimination kinetics of ciprofloxacin are similar for the immediate-release and the CIPRO
XR tablet. In studies comparing the CIPRO XR and immediate-release ciprofloxacin,
approximately 35% of an orally administered dose was excreted in the urine as unchanged drug
for both formulations. The urinary excretion of ciprofloxacin is virtually complete within 24
hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300
mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active
tubular secretion would seem to play a significant role in its elimination. Co-administration of
probenecid with immediate-release ciprofloxacin results in about a 50% reduction in the
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ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations
after oral dosing with the immediate-release tablet, only a small amount of the dose administered is
recovered from the bile as unchanged drug. An additional 1% to 2% of the dose is recovered
from the bile in the form of metabolites. Approximately 20% to 35% of an oral dose of
immediate-release ciprofloxacin is recovered from the feces within 5 days after dosing. This
may arise from either biliary clearance or transintestinal elimination.
Special Populations
Pharmacokinetic studies of the immediate-release oral tablet (single dose) and intravenous (single and
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (> 65 years) as compared to young adults. Cmax is increased 16% to 40%, and mean AUC
is increased approximately 30%, which can be at least partially attributed to decreased renal clearance
in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences
are not considered clinically significant. (See PRECAUTIONS, Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. No dose
adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg
CIPRO XR. For complicated urinary tract infection and acute uncomplicated pyelonephritis, where
1000 mg is the appropriate dose, the dosage of CIPRO XR should be reduced to CIPRO XR 500 mg
q24h in patients with creatinine clearance below 30 mL/min. (See DOSAGE AND
ADMINISTRATION.)
In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin
pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic
insufficiency, however, have not been fully elucidated. (See DOSAGE AND ADMINISTRATION.)
Drug-drug Interactions
Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS).
Previous studies with immediate-release ciprofloxacin have shown that concomitant administration of
ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum
theophylline levels and increased risk of a patient developing CNS or other adverse reactions.
Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after
caffeine administration. Absorption of ciprofloxacin is significantly reduced by concomitant
administration of multivalent cation-containing products such as magnesium/aluminum antacids,
sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, or products containing
calcium, iron, or zinc. (See WARNINGS: PRECAUTIONS, Drug Interactions and Information for
Patients, and DOSAGE AND ADMINISTRATION.)
Antacids: When CIPRO XR given as a single 1000 mg dose was administered two hours before, or
four hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg
magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19%
reduction, respectively, in the mean Cmax of ciprofloxacin. The reduction in the mean AUC was 24%
and 26%, respectively. CIPRO XR should be administered at least 2 hours before or 6 hours after
antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine)
chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron,
and multivitamin preparations with zinc. Although CIPRO XR may be taken with meals that include
milk, concomitant administration with dairy products or with calcium-fortified juices alone should be
avoided, since decreased absorption is possible. (See PRECAUTIONS, Information for Patients
and Drug Interactions, and DOSAGE AND ADMINISTRATION.)
Omeprazole: When CIPRO XR was administered as a single 1000 mg dose concomitantly with
omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and Cmax of
ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction
has not been determined. (See PRECAUTIONS, Drug Interactions.)
MICROBIOLOGY
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Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms.
The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and
topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication,
transcription, repair, and recombination. The mechanism of action of quinolones, including
ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides,
tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to
ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of
antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple-step mutation).
Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of
between < 10-9 to 1x10-6
.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus saprophyticus
Aerobic gram-negative microorganisms
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most
(≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of CIPRO XR in
treating clinical infections due to these microorganisms have not been established in adequate and
well-controlled clinical trials.
Aerobic gram-negative microorganisms
Citrobacter koseri
Morganella morganii
Citrobacter freundii
Proteus vulgaris
Edwardsiella tarda
Providencia rettgeri
Enterobacter aerogenes
Providencia stuartii
Enterobacter cloacae
Serratia marcescens
Klebsiella oxytoca
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin. The MIC values should be interpreted according to the
following criteria:
For testing Enterobacteriaceae, Enterococcus species, Pseudomonas aeruginosa, and
Staphylococcus species:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate (I)
≥ 4
Resistant
(R)
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
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compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures. Standard
ciprofloxacin powder should provide the following MIC values:
Microorganism
MIC Range (µg/mL)
Enterococcus faecalis
ATCC 29212
0.25 – 2.0
Escherichia coli
ATCC 25922
0.004 – 0.015
Staphylococcus aureus
ATCC 29213
0.12 – 0.5
Pseudomonas aeruginosa
ATCC 27853
0.25 – 1
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standard-
ized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper
disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus species, Pseudomonas aeruginosa, and
Staphylococcus species:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 – 20
Intermediate (I)
≤ 15
Resistant
(R)
Interpretation should be as stated above for results using dilution techniques. Interpretation involves cor-
relation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Microorganism
Zone Diameter (mm)
Escherichia coli
ATCC 25922
30 – 40
Staphylococcus aureus
ATCC 25923
22 – 30
Pseudomonas aeruginosa
ATCC 27853
25 – 33
INDICATIONS AND USAGE
CIPRO XR is indicated only for the treatment of urinary tract infections, including acute uncomplicated
pyelonephritis, caused by susceptible strains of the designated microorganisms as listed below. CIPRO XR
and ciprofloxacin immediate-release tablets are not interchangeable. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Uncomplicated Urinary Tract Infections (Acute Cystitis) caused by Escherichia coli, Proteus
mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus a
.
Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa a
.
Acute Uncomplicated Pyelonephritis caused by Escherichia coli.
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a Treatment of infections due to this organism in the organ system was studied in fewer than 10
patients.
THE SAFETY AND EFFICACY OF CIPRO XR IN TREATING INFECTIONS OTHER
THAN URINARY TRACT INFECTIONS HAS NOT BEEN DEMONSTRATED.
Appropriate culture and susceptibility tests should be performed before treatment in order to
isolate and identify organisms causing infection and to determine their susceptibility to
ciprofloxacin. Therapy with CIPRO XR may be initiated before results of these tests are
known; once results become available appropriate therapy should be continued. Culture and
susceptibility testing performed periodically during therapy will provide information not only
on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial
resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO XR and
other antibacterial drugs, CIPRO XR should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS, Drug
Interactions.)
WARNINGS
THE SAFETY AND EFFECTIVENESS OF CIPRO XR IN PEDIATRIC PATIENTS AND
ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND
NURSING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric
Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of ciprofloxacin caused
lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs
revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of
cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients
receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system
(CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal
thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients
receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with
all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.)
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SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING
CONCURRENT
ADMINISTRATION
OF
CIPROFLOXACIN
AND
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse effects have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose,
have been reported in patients receiving quinolone therapy. Some reactions were accompanied by
cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria,
and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic
reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and
airway management, including intubation, should be administered as indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along
with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded.
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of
hypersensitivity.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important
to consider this diagnosis in patients who present with diarrhea subsequent to the administration of
antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
If a diagnosis of pseudomembranous colitis is established, therapeutic measures should be initiated.
Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to
severe cases, consideration should be given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk
may be increased in patients receiving concomitant corticosteroids, especially the elderly.
Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture
of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or
tendon rupture has been excluded. Tendon rupture can occur during or after therapy with
quinolones, including ciprofloxacin.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMA-
COLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because
human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
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Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including:
nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information
for Patients, and Drug Interactions.)
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in
patients who are exposed to direct sunlight while receiving some members of the quinolone class of
drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
Prescribing CIPRO XR in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information for Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO XR should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO XR is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the course
of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the
full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable by CIPRO XR or other
antibacterial drugs in the future.
• that CIPRO XR may be taken with or without meals and to drink fluids liberally. As with other
quinolones, concurrent administration with magnesium/aluminum antacids, or sucralfate, VIDEX®
(didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other
products containing calcium, iron, or zinc should be avoided. CIPRO XR may be taken two hours
before or six hours after taking these products. (See CLINICAL PHARMACOLOGY, Drug-drug
Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions.)
CIPRO XR should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone since absorption of ciprofloxacin may be significantly reduced; however, CIPRO XR may be
taken with a meal that contains these products. (See CLINICAL PHARMACOLOGY, Drug-drug
Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions.)
• if the patient should forget to take CIPRO XR at the usual time, he/she may take the dose later
in the day. Do not take more than one CIPRO XR tablet per day even if a patient misses a
dose. Swallow the CIPRO XR tablet whole. DO NOT SPLIT, CRUSH, OR CHEW THE
TABLET.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue CIPRO XR at the first sign of a skin rash or other allergic reaction.
• to avoid excessive sunlight or artificial ultraviolet light while receiving CIPRO XR and to discontinue
therapy if phototoxicity occurs.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
• that if they experience pain, inflammation, or rupture of a tendon to discontinue treatment, to inform
their physician, and to rest and refrain from exercise.
• that CIPRO XR may cause dizziness and lightheadedness; therefore, patients should know how they
react to this drug before they operate an automobile or machinery or engage in activities requiring
mental alertness or coordination.
• that ciprofloxacin increase the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that CIPRO XR may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
notify their physician before taking CIPRO XR if there is a history of this condition.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
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significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
products such as magnesium/aluminum antacids, sucralfate, VIDEX® (didanosine) chewable/buffered
tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc
may substantially interfere with the absorption of the quinolone, resulting in serum and urine levels
considerably lower than desired. CIPRO XR should be administered at least 2 hours before or 6 hours
after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine)
chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron,
and multivitamin preparations with zinc. (See CLINICAL PHARMACOLOGY, Drug-drug
Interactions,
PRECAUTIONS,
Information
for
Patients,
and
DOSAGE
AND
ADMINISTRATION.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
ciprofloxacin.
Absorption of the CIPRO XR tablet was slightly diminished (20%) when given concomitantly with
omeprazole. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.)
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions,
resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase
the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate
therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to
reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin, and the test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
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Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice
at daily oral dose levels of 250 and 750 mg/kg, respectively (approximately 2 and 3 -fold greater than
the 1000 mg daily human dose based upon body surface area).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to the
maximum recommended daily human dose of 1000 mg based upon mg/m2), as opposed to 34 weeks
when animals were treated with both UVA and vehicle. The times to development of skin tumors
ranged from 16-32 weeks in mice treated concomitantly with UVA and other quinolones.
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance
of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (1.0 times the highest
recommended daily human dose of 1000 mg based upon body surface area) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS - the Teratogen Information System – concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state there is no risk.
A controlled prospective observational study followed 200 women exposed to
fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during
gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with
increased risk of major malformations. The reported rates of major congenital malformations
were 2.2% for the fluoroquinolone group and 2.6% for the control group (background
incidence of major malformations is 1-5%). Rates of spontaneous abortions, prematurity and
low birth weight did not differ between the groups and there were no clinically significant
musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure
(93% first trimester exposures).There were 70 ciprofloxacin exposures, all within the first
trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to
fluoroquinolones overall were both within background incidence ranges. No specific patterns
of congenital abnormalities were found. The study did not reveal any clear adverse reactions
due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the
risk for the less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless potential benefit justifies the potential risk to both fetus and mother (see
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WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.7 and
0.4 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and
have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and
100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an
increased incidence of abortion, but no teratogenicity was observed at either dose. After intravenous
administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no
embryotoxicity or teratogenicity was observed.
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of CIPRO XR in pediatric patients and adolescents less than
18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. (See
WARNINGS.)
Geriatric Use: In a large, prospective, randomized CIPRO XR clinical trial in complicated urinary tract
infections, 49% (509/1035) of the patients were 65 and over, while 30% (308/1035) were 75 and over.
No overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and clinical experience with other formulations of ciprofloxacin has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of
adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function. However, since some older
individuals experience reduced renal function by virtue of their advanced age, care should be taken in
dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000
mg CIPRO XR. Most adverse events reported were described as mild to moderate in severity and
required no treatment. The overall incidence, type and distribution of adverse events were similar in
patients receiving both 500 mg and 1000 mg of CIPRO XR. Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be
directly compared to rates observed in clinical trials of another drug and may not reflect the rates
observed in practice. The adverse reaction information from clinical studies does, however, provide a
basis for identifying the adverse events that appear to be related to drug use and for approximating
rates.
In the clinical trial of uncomplicated urinary tract infection, CIPRO XR (500 mg once daily) in 444
patients was compared to ciprofloxacin immediate-release tablets (250 mg twice daily) in 447 patients
for 3 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 0.2%
(1/444) of patients in the CIPRO XR arm and in 0% (0/447) of patients in the control arm.
In the clinical trial of complicated urinary tract infection and acute uncomplicated pyelonephritis,
CIPRO XR (1000 mg once daily) in 517 patients was compared to ciprofloxacin immediate-release
tablets (500 mg twice daily) in 518 patients for 7 to 14 days. Discontinuations due to adverse reactions
thought to be drug-related occurred in 3.1% (16/517) of patients in the CIPRO XR arm and in 2.3%
(12/518) of patients in the control arm. The most common reasons for discontinuation in the CIPRO
XR arm were nausea/vomiting (4 patients) and dizziness (3 patients). In the control arm the most
common reason for discontinuation was nausea/vomiting (3 patients).
In these clinical trials, the following events occurred in ≥ 2% of all CIPRO XR patients, regardless of
drug relationship: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%) and
vaginal moniliasis (2%).
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Adverse events, judged by investigators to be at least possibly drug-related, occurring in greater than or
equal to 1% of all CIPRO XR treated patients were: nausea (3%), diarrhea (2%), headache (1%),
dyspepsia (1%), dizziness (1%), and vaginal moniliasis (1%). Vomiting (1%) occurred in the 1000 mg
group.
Additional uncommon events, judged by investigators to be at least possibly drug-related, that occurred
in less than 1% of CIPRO XR treated patients were:
BODY AS A WHOLE: abdominal pain, asthenia, malaise, photosensitivity reaction
CARDIOVASCULAR: bradycardia, migraine, syncope
DIGESTIVE: anorexia, constipation, dry mouth, flatulence, liver function tests abnormal, thirst
HEMIC/LYMPHATIC: prothrombin decrease
CENTRAL NERVOUS SYSTEM: abnormal dreams, depersonalization, depression, hypertonia,
incoordination, insomnia, somnolence, tremor, vertigo
METABOLIC: hyperglycemia
SKIN/APPENDAGES: dry skin, maculopapular rash, pruritus, rash, skin disorder, urticaria,
vesiculobullous rash
SPECIAL SENSES: diplopia, taste perversion
UROGENITAL: dysmenorrhea, hematuria, kidney function abnormal, vaginitis
The following additional adverse events, some of them life threatening, regardless of incidence or
relationship to drug, have been reported during clinical trials and from worldwide post-marketing
experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy
durations, and all indications). Because these reactions have been reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to
drug exposure. The events in alphabetical order are:
abnormal gait, achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria
to anaphylactic reactions and including life-threatening anaphylactic shock), amylase increase, anemia,
angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding
diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral),
candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis,
chills, cholestatic jaundice, chromatopsia, confusion, convulsion, delirium, drowsiness, dysphagia,
dysphasia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck,
pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed
eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia,
hallucinations, hearing loss, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure,
hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia,
hypesthesia, hypotension, ileus, interstitial nephritis, intestinal perforation, jaundice, joint stiffness,
lethargy, lightheadedness, lipase increase, lymphadenopathy, manic reaction, marrow depression,
migraine, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration,
pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation,
pancreatitis, pancytopenia, paranoia, paresthesia, peripheral neuropathy, perspiration (increased),
petechia, phlebitis, phobia, pleural effusion, polyuria, postural hypotension, prothrombin time
prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after
antimicrobial treatment), pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest,
respiratory distress, restlessness, serum sickness-like reaction, Stevens-Johnson syndrome, sweating,
tachycardia, taste loss, tendinitis, tendon rupture, tinnitus, torsade de pointes, toxic epidermal
necrolysis (Lyell’s syndrome), toxic psychosis, twitching, unresponsiveness, urethral bleeding, urinary
retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity
(decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights).
Laboratory Changes:
The following adverse laboratory changes, in alphabetical order, regardless of incidence or relationship
to drug, have been reported in patients given ciprofloxacin (includes all formulations, all dosages, all
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drug-therapy durations, and all indications):
Decreases in blood glucose, BUN, hematocrit, hemoglobin, leukocyte counts, platelet counts,
prothrombin time, serum albumin, serum potassium, total serum protein, uric acid.
Increases in alkaline phosphatase, ALT (SGPT), AST (SGOT), atypical lymphocyte counts, blood
glucose, blood monocytes, BUN, cholesterol, eosinophil counts, LDH, platelet counts, prothrombin
time, sedimentation rate, serum amylase, serum bilirubin, serum calcium, serum cholesterol, serum
creatine phosphokinase, serum creatinine, serum gamma-glutamyl transpeptidase (GGT), serum
potassium, serum theophylline (in patients receiving theophylline concomitantly), serum triglycerides,
uric acid.
Others: albuminuria, change in serum phenytoin, crystalluria, cylindruria, immature WBCs,
leukocytosis, methemoglobinemia, pancytopenia.
OVERDOSAGE
In the event of acute excessive overdosage, reversible renal toxicity has been reported in some cases.
The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be
carefully observed and given supportive treatment, including monitoring of renal function and
administration of magnesium or calcium containing antacids which can reduce the absorption of
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
is removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats,
and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral
doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs
observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed
in these animals, occurring 10-14 days after dosing.
DOSAGE AND ADMINISTRATION
CIPRO XR and ciprofloxacin immediate-release tablets are not interchangeable. Cipro XR should be
administered orally once daily as described in the following Dosage Guidelines table:
DOSAGE GUIDELINES
Indication
Unit Dose
Frequency
Usual Duration
Uncomplicated Urinary Tract Infection
500 mg
Q24h
3 Days
(Acute Cystitis)
Complicated Urinary Tract Infection
1000 mg
Q24h
7-14 Days
Acute Uncomplicated Pyelonephritis
1000 mg
Q24h
7-14 Days
Patients whose therapy is started with CIPRO I.V. for urinary tract infections may be switched to
CIPRO XR when clinically indicated at the discretion of the physician.
CIPRO XR should be administered at least 2 hours before or 6 hours after antacids containing
magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or
pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations
with zinc. Although CIPRO XR may be taken with meals that include milk, concomitant administration
with dairy products alone, or with calcium-fortified products should be avoided, since decreased
absorption is possible. A 2-hour window between substantial calcium intake (> 800 mg) and dosing with
CIPRO XR is recommended. CIPRO XR should be swallowed whole. DO NOT SPLIT, CRUSH,
OR CHEW THE TABLET. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions,
PRECAUTIONS, Drug Interactions and Information for Patients.)
Impaired Renal Function:
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
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partially cleared through the biliary system of the liver and through the intestine. These alternate
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with
renal impairment. No dosage adjustment is required for patients with uncomplicated urinary tract
infections receiving 500 mg CIPRO XR. In patients with complicated urinary tract infections and acute
uncomplicated pyelonephritis, who have a creatinine clearance of < 30 mL/min, the dose of CIPRO
XR should be reduced from 1000 mg to 500 mg daily. For patients on hemodialysis or peritoneal
dialysis, administer CIPRO XR after the dialysis procedure is completed. (See CLINICAL
PHARMACOLOGY, Special Populations, and PRECAUTIONS, Geriatric Use.)
Impaired Hepatic Function:
No dosage adjustment is required with CIPRO XR in patients with stable chronic cirrhosis. The
kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully
elucidated. (See CLINICAL PHARMACOLOGY, Special Populations.)
HOW SUPPLIED
CIPRO XR is available as nearly white to slightly yellowish, film-coated, oblong-shaped tablets
containing 500 mg or 1000 mg ciprofloxacin. The 500 mg tablet is coded with the word “BAYER” on
one side and “C500 QD” on the reverse side. The 1000 mg tablet is coded with the word “BAYER” on
one side and “C1000 QD” on the reverse side.
Strength
NDC Code
Bottles of 50
500 mg
0085-1775-02
Bottles of 100
500 mg
0085-1775-01
Bottles of 50
1000 mg
0085-1778-03
Bottles of 100
1000 mg
0085-1778-01
Unit Dose Pack of 30
1000 mg
0085-1778-02
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a
subsequent study in beagles, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human
urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been noted after sin-
gle oral doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no
nephropathological changes were noted; however, nephropathy was observed after dosing at 20
mg/kg/day for the same duration.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Uncomplicated Urinary Tract Infections (acute cystitis)
CIPRO XR was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in
a randomized, double-blind, controlled clinical trial conducted in the US. This study compared CIPRO
XR (500 mg once daily for three days) with ciprofloxacin immediate-release tablets (CIPRO® 250 mg
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BID for three days). Of the 905 patients enrolled, 452 were randomly assigned to the CIPRO XR
treatment group and 453 were randomly assigned to the control group. The primary efficacy variable
was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at
test-of-cure (Day 4 -11 Post-therapy).
The bacteriologic eradication and clinical success rates were similar between CIPRO XR and the
control group. The eradication and clinical success rates and their corresponding 95% confidence
intervals for the differences between rates (CIPRO XR minus control group) are given in the following
table:
CIPRO XR 500 mg
QD x 3 Days
CIPRO 250 mg
BID x 3 Days
Randomized Patients
452
453
Per Protocol Patients†
199
223
Bacteriologic Eradication at TOC (n/N)*
188/199 (94.5%)
209/223 (93.7%)
CI [-3.5%, 5.1%]
Bacteriologic Eradication
(by organism) at TOC (n/N)**
E. coli
156/160 (97.5%)
176/181 (97.2%)
E. faecalis
10/11 (90.9%)
17/21 (81.0%)
P. mirabilis
11/12 (91.7%)
7/7 (100%)
S. saprophyticus
6/7 (85.7%)
9/9 (100%)
Clinical Response at TOC (n/N)***
189/199 (95.0%)
204/223 (91.5%)
CI [-1.1%, 8.1%]
*
n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/
total number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline
organism
*** n/N = patients with clinical success /total number of patients
† The presence of a pathogen at a level of ≥ 105 CFU/mL was required for microbiological evaluability
criteria, except for S. saprophyticus (≥ 104 CFU/mL).
Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis
CIPRO XR was evaluated for the treatment of complicated urinary tract infections (cUTI) and acute
uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted
in the US and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and
compared CIPRO XR (1000 mg once daily for 7 to 14 days) with immediate-release ciprofloxacin
(500 mg BID for 7 to 14 days). The primary efficacy endpoint for this trial was bacteriologic
eradication of the baseline organism(s) with no new infection or superinfection at 5 to 11 days
post-therapy (test-of-cure or TOC) for the Per Protocol and Modified Intent-To-Treat (MITT)
populations.
The Per Protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative
organism(s) at baseline present at ≥ 105 CFU/mL, no inclusion criteria violation, a valid test-of-cure
urine culture within the TOC window, an organism susceptible to study drug, no premature
discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria).
More patients in the CIPRO XR arm than in the control arm were excluded from the Per Protocol
population and this should be considered in the interpretation of the study results. Reasons for
exclusion with the greatest discrepancy between the two arms were no valid test-of-cure urine culture,
an organism resistant to the study drug, and premature discontinuation due to adverse events.
An analysis of all patients with a causative organism(s) isolated at baseline and who received study
medication, defined as the MITT population, included 342 patients in the CIPRO XR arm and 324
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patients in the control arm. Patients with missing responses were counted as failures in this analysis. In
the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59.0%) versus 156/248
(62.9%) in CIPRO XR and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was
184/271 (67.9%) for CIPRO XR and 182/248 (73.4%) for control arm, respectively [97.5% CI*
(-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71
(66.2%) and 58/76 (76.3%) for CIPRO XR and control arm, respectively [97.5% CI* (-26.8%, 6.5%)].
Clinical cure at TOC was 50/71 (70.4%) for CIPRO XR and 58/76 (76.3%) for the control arm [97.5%
CI* (-22.0%, 10.4%)].
* confidence interval of the difference in rates (CIPRO XR minus control).
In the Per Protocol population, the differences between CIPRO XR and the control arm in
bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients.
The bacteriologic eradication rate for cUTI patients was higher in the CIPRO XR arm than in the
control arm. For AUP patients, the bacteriologic eradication rate was lower in the CIPRO XR arm than
in the control arm. This inconsistency was not observed between the two treatment groups for clinical
cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for CIPRO XR and the
control arm, respectively.
The bacterial eradication and clinical cure rates by infection type for CIPRO XR and the control arm at
the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates
(CIPRO XR minus control arm) are given below for the Per Protocol population analysis:
CIPRO XR 1000 mg QD
CIPRO 500 mg BID
Randomized Patients
521
521
Per Protocol Patients^
206
229
cUTI Patients
Bacteriologic Eradication at TOC (n/N)*
148/166 (89.2%)
144/177 (81.4%)
CI [-0.7%, 16.3%]
Bacteriologic Eradication
(by organism) at TOC (n/N)**
E. coli
91/94 (96.8%)
90/92 (97.8%)
K. pneumoniae
20/21 (95.2%)
19/23 (82.6%)
E. faecalis
17/17 (100%)
14/21 (66.7%)
P. mirabilis
11/12 (91.6%)
10/10 (100%)
P. aeruginosa
3/3 (100%)
3/3 (100%)
Clinical Cure at TOC (n/N)***
159/166 (95.8%)
161/177 (91.0%)
CI [-1.1%, 10.8%]
AUP Patients
Bacteriologic Eradication at TOC (n/N)*
35/40 (87.5%)
51/52 (98.1%)
CI [-34.8%, 6.2%]
Bacteriologic Eradication of E. coli
at TOC (n/N)**
35/36 (97.2%)
41/41 (100%)
Clinical Cure at TOC (n/N)***
39/40 (97.5%)
50/52 (96.2%)
CI [-15.3%, 21.1%]
^ Patients excluded from the Per Protocol population were primarily those with no causative organism(s)
at baseline or no organism present at ≥ 105 CFU/mL at baseline, inclusion criteria violation, no valid
test-of-cure urine culture within the TOC window, an organism resistant to study drug, premature
discontinuation due to an adverse event, lost to follow-up, or non-compliance with dosage regimen
(among other criteria).
* n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total
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number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism
***n/N = patients with clinical success /total number of patients
Of the 166 cUTI patients treated with CIPRO XR, 148 (89%) had the causative organism(s) eradicated, 8
(5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections.
Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated,
16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new
infections. Of the 40 patients with AUP treated with CIPRO XR, 35 (87.5%) had the causative
organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5
CIPRO XR AUP patients without eradication at TOC, 4 were considered clinical cures and did not
receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had
the causative organism(s) eradicated. One patient (2%) had persistence.
References: 1. NCCLS, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically-Sixth Edition. Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS,
Wayne, PA, January, 2003.
2. NCCLS, Performance Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition.
Approved Standard NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.
PATIENT INFORMATION ABOUT
CIPRO® XR
(ciprofloxacin extended-release tablets)
This section contains important patient information about CIPRO XR and should be read completely
before you begin treatment. This section does not take the place of discussion with your doctor or
health care professional about your medical condition or your treatment. This section does not list all
benefits and risks of CIPRO XR. CIPRO XR can be prescribed only by a licensed health care
professional. Your doctor has prescribed CIPRO XR only for you.
CIPRO XR is intended only to treat urinary tract infections and acute uncomplicated pyelonephritis
(also known as a kidney infection). It should not be used to treat other infections. Do not give it to other
people even if they have a similar condition. Do not use it for a condition for which it was not
prescribed. If you have any concerns about your condition or your medicine, ask your doctor. Only your
doctor can determine if CIPRO XR is right for you.
What is CIPRO XR?
CIPRO XR is an antibiotic in the quinolone class that contains the active ingredient ciprofloxacin.
CIPRO XR is specifically formulated to be taken just once daily to kill bacteria causing infection in the
urinary tract. CIPRO XR has been shown in clinical trials to be effective in the treatment of urinary
tract infections. You should contact your doctor if your condition is not improving while taking
CIPRO XR.
CIPRO XR tablets are nearly white to slightly yellowish, film-coated, oblong-shaped tablets. CIPRO
XR is available in 500 mg and 1000 mg tablet strengths.
How and when should I take CIPRO XR?
CIPRO XR should be taken once a day for three (3) to fourteen (14) days depending on your infection.
Take CIPRO XR at approximately the same time each day with food or on an empty stomach. CIPRO
XR should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone;
however, CIPRO XR may be taken with a meal that contains these products. Should you forget to take it
at the usual time, you may take your dose later in the day. Do not take more than one CIPRO XR tablet
per day even if you missed a dose. Swallow the CIPRO XR tablet whole. DO NOT SPLIT, CRUSH,
OR CHEW THE TABLET.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
You should take CIPRO XR for as long as your doctor prescribes it, even after you start to feel better.
Stopping an antibiotic too early may result in failure to cure your infection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Who should not take CIPRO XR?
You should not take CIPRO XR if you have ever had a severe reaction to any of the group of antibiotics
known as “quinolones.” You should also not take CIPRO if you are also taking a medication called
tizanidine (Zanaflex® ), as excessive side effects from tizanidine are likely to occur.
CIPRO XR is not recommended for use during pregnancy or nursing, as the effects on the unborn child
or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking CIPRO XR,
talk to your doctor before taking this medication.
CIPRO XR is not recommended for persons less than 18 years of age.
What are the possible side effects of CIPRO XR?
CIPRO XR is generally well tolerated. The most common side effects, which are usually mild, include
nausea, headache, dyspepsia, dizziness, vaginal yeast infection and diarrhea. If diarrhea persists, call
your health care professional. Antibiotics of the quinolone class may also cause vomiting, rash, and
abdominal pain/discomfort.
You should be careful about driving or operating machinery until you are sure CIPRO XR is not
causing dizziness.
Rare cases of allergic reactions have been reported in patients receiving quinolones, including
ciprofloxacin, even after just one dose. If you develop hives, difficulty breathing, or other symptoms of
a severe allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should
stop taking CIPRO XR and call your health care professional.
Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light
such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet light
while you are taking CIPRO XR.
Ciprofloxacin has been rarely associated with inflammation of tendons. If you experience pain,
swelling or rupture of a tendon, you should stop taking CIPRO XR and call your health care
professional.
Convulsions have been reported in patients receiving quinolone antibiotics including ciprofloxacin. If
you have experienced convulsions in the past, be sure to let your physician know that you have a
history of convulsions. Quinolones, including ciprofloxacin, have been rarely associated with other
central nervous system events including confusion, tremors, hallucinations, and depression.
If you notice any side effects not mentioned in this section, or if you have any concerns about side
effects you may be experiencing, please inform your health care professional.
What about other medications I am taking?
CIPRO XR can affect how other medicines work. Tell your doctor about all other prescriptions and
nonprescription medicines or supplements you are taking. This is especially important if you are taking
tizanidine (Zanaflex® ) or theophylline or VIDEX® (didanosine) chewable/buffered tablets or pediatric
powder. Other medications including warfarin, glyburide, and phenytoin may also interact with
CIPRO XR. You should not take Cipro if you are also taking tizanidine.
Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium, alu-
minum, iron or zinc can interfere with the absorption of CIPRO XR and may prevent it from working.
You should take CIPRO XR either 2 hours before or 6 hours after taking these products.
Remember:
Do not give CIPRO XR to anyone other than the person for whom it was prescribed.
Complete the course of CIPRO XR even if you are feeling better.
Keep CIPRO XR and all medications out of reach of children.
This information does not take the place of discussions with your doctor or health care professional
about your medication or treatment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx Only
Manufactured by:
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Made in Germany
Distributed by:
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
Corporation.
XXXX
Bay o 9867/q 3939
9/05
XXXXX
©2005 Bayer Pharmaceuticals Corporation
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:07.003890
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019537s60,019847s36,019857s41,020780s20,021473s13lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 36}
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
structural formula
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate (I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
provide the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
aeruginosa.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
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Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If
these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and
appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in
patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction).
(See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
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fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
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Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
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Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
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malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
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fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
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SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with flouroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
Reference ID: 2910764
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decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
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Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
7-14 Days
7-14 Days
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
≥ 4-6 Weeks
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
28 Days
Empirical Therapy
in
Severe
Febrile Neutropenic
Patients
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
Not to exceed
q8h
q4h
7-14 Days
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
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750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
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(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
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5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V.
is available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Hospira, Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Baxter Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1759-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1782-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
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* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
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PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
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Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
Reference ID: 2910764
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95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial
Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000.
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
6. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
8. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO can cause side effects that may
be serious or even cause death. If you get any of the following serious side effects, get medical help right
away. Talk with your healthcare provider about whether you should continue to take CIPRO.
• Tendon rupture or swelling of the tendon (tendinitis)
• Tendons are tough cords of tissue that connect muscles to bones.
• Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles),
shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone
antibiotics, including CIPRO. The risk of getting tendon problems is higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in
patients who take fluoroquinolones who do not have the above risk factors.
• Other reasons for tendon ruptures can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation.
Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by your healthcare provider.
Avoid exercise and using the affected area. The most common area of pain and swelling is the
Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your
healthcare provider about the risk of tendon rupture with continued use of CIPRO. You may need a
different antibiotic that is not a fluoroquinolone to treat your infection.
• Tendon rupture can happen while you are taking or after you have finished taking CIPRO. Tendon
ruptures have happened up to several months after patients have finished taking their
fluoroquinolone.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
• Worsening of myasthenia gravis (a disease which causes muscle weakness). Fluoroquinolones
like CIPRO may cause worsening of myasthenia gravis symptoms, including muscle weakness and
breathing problems. Call your healthcare provider right away if you have any worsening muscle
weakness or breathing problems.
See the section “What are the possible side effects of CIPRO?” for more information about side
effects.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain germs
called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon
(musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be used as
the first choice of antibiotic medicine in children under 18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children under 18 years
old, except to treat specific serious infections, such as complicated urinary tract infections and to
prevent anthrax disease after breathing the anthrax bacteria germ (inhalational exposure). It is not
known if CIPRO XR is safe and works in children under 18 years of age.
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in
the sinuses and lungs, such as the common cold or flu. Antibiotics, including CIPRO, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are taking
CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
• have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic
to any of the ingredients in CIPRO. Ask your healthcare provider if you are not sure. See the list of
ingredients in CIPRO at the end of this Medication Guide.
• also take a medicine called tizanidine (Zanaflex®). Serious side effects from tizanidine are likely to
happen.
What should I tell my healthcare provider before taking CIPRO?
See “What is the most important information I should know about CIPRO?”
Tell your healthcare provider about all your medical conditions, including if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis)
• have central nervous system problems (such as epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
Reference ID: 2910764
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• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other medicines
can affect each other causing side effects. Especially tell your healthcare provider if you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are
NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may increase your
risk of central nervous system effects and seizures. See "What are the possible side effects of
CIPRO?".
• a blood thinner (warfarin, Coumadin®, Jantoven®)
• tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine. See “Who
should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible side
effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended Phenytoin
Sodium®, Prompt Penytoin Sodium®, Phenytek®)
• products that contain caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the possible side
effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of
tendon injury. See “What is the most important information I should know about CIPRO?”
• methotrexate (Trexall®)
• Probenecid (Probalan®, Col-probenecid®)
• Metoclopromide (Reglan®, Reglan ODT®)
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from working correctly.
Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after taking these
products:
• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc
• sucralfate (Carafate®)
•
didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow the
tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day. Shake
the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to make sure the
suspension is mixed well. Close the bottle completely after use.
Reference ID: 2910764
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• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet whole. Do
not split, crush or chew the tablet. Tell your healthcare provider if you can not swallow the tablet
whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60 minutes,
as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you finish your
prescribed treatment, unless:
• you have tendon effects (see “What is the most important information I should know about
CIPRO?”),
• you have a serious allergic reaction (see “What are the possible side effects of CIPRO?”), or
•
your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will
become resistant to CIPRO. If this happens, CIPRO and other antibiotic medicines may not work in
the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember. Do not
take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than one dose
in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V. after
being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance of getting anthrax
disease or worsening of the disease after you are exposed to the anthrax bacteria germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking CIPRO without
talking with your healthcare provider. If you stop taking CIPRO too soon, it may not keep you from
getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or I.V. When taking
your CIPRO to prevent anthrax infection, you and your healthcare provider should talk about
whether the risks of stopping CIPRO too soon are more important than the risks of side effects with
CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your healthcare
provider should decide whether the benefits of taking CIPRO Tablets, Oral Suspension or I.V. for
anthrax are more important than the risks.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other
activities that require mental alertness or coordination until you know how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make your skin
sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get
severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking
CIPRO, call your healthcare provider right away. You should use a sunscreen and wear a hat and
clothes that cover your skin if you have to be in sunlight.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the most
important information I should know about CIPRO?”
Other serious side effects of CIPRO include:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics including CIPRO. Tell
your healthcare provider if you have a history of seizures. Ask your healthcare provider whether
taking CIPRO will change your risk of having a seizure.
Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of
CIPRO. Talk to your healthcare provider right away if you get any of these side effects, or other
changes in mood or behavior:
• feel dizzy
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
• trouble sleeping
• nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even after only
one dose. Stop taking CIPRO and get emergency medical help right away if you get any of the
following symptoms of a severe allergic reaction:
• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right away if
you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can
be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking CIPRO at the
first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious
reaction to CIPRO.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular
heartbeat), or if you faint. CIPRO may cause a rare heart problem known as prolongation of the QT
interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of
this event are higher in people:
• who are elderly
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody
stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or
more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones,
including CIPRO. Talk with your healthcare provider right away if you get any of the following
symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
• pain
• burning
• tingling
• numbness
•
weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes medicine
glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia)
which can sometimes be severe. Tell your healthcare provider if you get low blood sugar with
CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18 years old.
Tell your child’s healthcare provider if your child has any joint problems during or after treatment
with CIPRO.
The most common side effects of CIPRO include:
• nausea
• headache
• diarrhea
• vomiting
• vaginal yeast infection
• changes in liver function tests
•
pain or discomfort in the abdomen
These are not all the possible side effects of CIPRO. Tell your healthcare provider about any side effect
that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would like
more information about CIPRO, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about CIPRO that is written for healthcare professionals. For
more information go to www.CIPRO.com or call 1-800-526-4099.
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone,
magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20. Diluentmedium-chain triglycerides, sucrose,
lecithin, water, and strawberry flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH adjustment
Revised February 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for: company logo
Bayer HealthCare Pharmaceuticals Inc.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Wayne, NJ 07470
Manufactured in Germany
or
Manufactured in Norway
By Fresenius Kabi Norge AS
NO - 1753 Halden, Norway
Distributed by:
company logo
Whitehouse Station, NJ 08889, USA
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by
Schering Corporation.
Rx Only
02/11
©2011 Bayer HealthCare Pharmaceuticals Inc.
Printed In U.S.A.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:07.766539
|
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11,772
|
CIPRO®
(ciprofloxacin hydrochloride)
TABLETS
CIPRO®
(ciprofloxacin*)
ORAL SUSPENSION
81532304, R.1
02/09
WARNING:
Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis
and tendon rupture in all ages. This risk is further increased in older patients usually
over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants (See WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO
Tablets and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
DESCRIPTION
CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light
yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is
C17H18FN3O3•HCl•H2Oand its chemical structure is as follows: Chemical Structure
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light
yellow crystalline substance and its chemical structure is as follows: Chemical Structure
CIPRO film-coated tablets are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent)
strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are cornstarch,
microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, hypromellose,
titanium dioxide, and polyethylene glycol.
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish
suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of
Bayer Response 12 Feb 2009
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See instructions for
USE/HANDLING). The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20.
Diluentmedium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
* Does not comply with USP with regard to “loss on drying” and “residue on ignition”.
CLINICAL PHARMACOLOGY
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal
tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss
by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are
shown in the chart for the 250 mg to 1000 mg dose range.
Maximum
Area
Dose
Serum Concentration Under Curve (AUC)
(mg)
(µg/mL)
(µg•hr/mL)
250
1.2
4.8
500
2.4
11.6
750
4.3
20.2
1000
5.4
30.8
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimi
nation half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations
increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been
shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400
mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed
with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that
produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
Steady-state Pharmacokinetic Parameters
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7a
12.7a
31.6b
32.9c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
aAUC 0-12h
bAUC 24h=AUC0-12h x 2
cAUC 24h=AUC0-8h x 3
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high
enough to cause significant protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations
often exceed serum concentrations in both men and women, particularly in genital tissue including the
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prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of
the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the
cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism: Four metabolites have been identified in human urine which together account for
approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less
active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450
1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs
primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs
and could lead to clinically significant adverse events of the coadministered drug (see
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL during
the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion
of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin,
which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120
mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately
20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from
either biliary clearance or transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in the
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather
than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The
overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The
pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Concurrent
administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the
bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS).
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other
adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See WARNINGS: PRECAUTIONS.)
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
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multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the
increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These
differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
acute hepatic insufficiency, however, have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following
microorganisms, both in vitro and in clinical infections as described in the INDICATIONS
AND USAGE section of the package insert for CIPRO (ciprofloxacin hydrochloride) Tablets
and CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
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Streptococcus pyogenes
Aerobic gram-negative microorganisms
Campylobacter jejuni
Proteus mirabilis
Citrobacter diversus
Proteus vulgaris
Citrobacter freundii
Providencia rettgeri
Enterobacter cloacae
Providencia stuartii
Escherichia coli
Pseudomonas aeruginosa
Haemophilus influenzae
Salmonella typhi
Haemophilus parainfluenzae
Serratia marcescens
Klebsiella pneumoniae
Shigella boydii
Moraxella catarrhalis
Shigella dysenteriae
Morganella morganii
Shigella flexneri
Neisseria gonorrhoeae
Shigella sonnei
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains only)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Pasteurella multocida
Aeromonas hydrophila
Salmonella enteritidis
Edwardsiella tarda
Vibrio cholerae
Enterobacter aerogenes
Vibrio parahaemolyticus
Klebsiella oxytoca
Vibrio vulnificus
Legionella pneumophila
Yersinia enterocolitica
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
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For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible
aeruginosa a:
Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
MIC (µg/mL)
≤1
2
≥4
Interpretation
Susceptible
(S)
Intermediate (I)
Resistant
(R)
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
MIC (µg/mL)
Interpretation
≤1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
MIC (µg/mL)
Interpretation
≤ 0.06
Susceptible
(S)
0.12 – 0.5
Intermediate (I)
≥1
Resistant
(R)
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
growth supplement.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
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Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
C. jejunib
ATCC 33560
0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeaec
ATCC 49226
0.001-0.008
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
b C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller
Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37oC for
48 hours and for 42oC at 24 hours2, respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1%
defined growth supplement in a 5% CO2 environment at 35-37oC for 20-24 hours3.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 – 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using
Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)3.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
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For testing Neisseria gonorrhoeaec:
Zone Diameter (mm)
Interpretation
≥ 41
Susceptible
(S)
28 – 40
Intermediate (I)
≤ 27
Resistant
(R)
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined
growth supplement.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30 – 40
H. influenzaea
ATCC 49247
34 – 42
N. gonorrhoeaeb
ATCC 49226
48 – 58
P. aeruginosa
ATCC 27853
25 – 33
S. aureus
ATCC 25923
22 – 30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)3.
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226
performed by disk diffusion using GC agar base and 1% defined growth supplement.
INDICATIONS AND USAGE
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
saprophyticus.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus
pneumoniae, or Moraxella catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
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Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
morganii,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
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Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
Shigella boydii †, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial
therapy is indicated.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been
demonstrated.
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.5
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
significant outcome, efficacy was studied in fewer than 10 patients.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in
order to isolate and identify organisms causing infection and to determine their susceptibility to
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
results become available appropriate therapy should be continued. As with other drugs, some strains of
Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin.
Culture and susceptibility testing performed periodically during therapy will provide information not
only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial
resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by susceptible bacteria. When culture and susceptibility information are available, they should
be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO, are associated
with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most
frequently involves the Achilles tendon, and rupture of the Achilles tendon may require
surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the
biceps, the thumb, and other tendon sites have also been reported. The risk of developing
fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants. Factors, in addition to age and corticosteroid use, that may
independently increase the risk of tendon rupture include strenuous physical activity, renal
failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon
rupture have also occurred in patients taking fluoroquinolones who do not have the above risk
factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO should be discontinued
if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should
be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare
provider regarding changing to a non-quinolone antimicrobial drug.
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline,
methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and
could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
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risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus,
and respiratory failure. Although similar serious adverse effects have been reported in patients
receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin
cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be
administered as indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of
multiple doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or
any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CIPRO, and may range in
severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after
the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
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Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after
three months.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions,
the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema,
exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V”
area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with
the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these
sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs
(See ADVERSE REACTIONS/Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Information for Patients:
Patients should be advised:
•to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or
weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
•that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
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to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be
taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
other antibacterial drugs in the future.
•that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered
drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may
be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken
with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of
ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that
contains these products.
•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones.
Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or
UVA/B treatment) while taking quinolones. If patients need to be outdoors while using
quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and
discuss other sun protection measures with their physician. If a sunburn-like reaction or skin
eruption occurs, patients should contact their physician.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know
how they react to this drug before they operate an automobile or machinery or engage in
activities requiring mental alertness or coordination.
•that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
•that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
• that diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can
develop watery and bloody stools (with or without stomach cramps and fever) even as late as
two or more months after having taken the last dose of the antibiotic. If this occurs, patients
should contact their physician as soon as possible.
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Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc
may substantially decrease its absorption, resulting in serum and urine levels considerably lower than
desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents
with ciprofloxacin.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions,
resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in
the level of ciprofloxacin in the serum. This should be considered if patients are receiving both
drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase
the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate
therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to
reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin, and the test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79Cell HGPRT Test (Negative)
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Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maxi
mum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
weeks in mice treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance
of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and
well-controlled studies in pregnant women. An expert review of published data on experiences with
ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that
therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and
quality of data=fair), but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones
(52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero
exposure to fluoroquinolones during embryogenesis was not associated with increased risk of
major malformations. The reported rates of major congenital malformations were 2.2% for the
fluoroquinolone group and 2.6% for the control group (background incidence of major
malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not
differ between the groups and there were no clinically significant musculoskeletal dysfunctions up
to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
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exposed to ciprofloxacin during pregnancy.8,9 However, these small post-marketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate
the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during
pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and
100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based
upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended
therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including events related to joints and/or surrounding tissues. The
rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless
of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
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and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age
were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders
including tendon rupture when being treated with a fluoroquinolone such as CIPRO. This risk
is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or
tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur
during or after completion of therapy; cases occurring up to several months after
fluoroquinolone treatment have been reported. Caution should be used when prescribing
CIPRO to elderly patients especially those on corticosteroids. Patients should be informed of
this potential side effect and advised to discontinue CIPRO and contact their healthcare
provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning,
WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals on any drug therapy cannot be ruled out.
Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
reactions may be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function. However, since some
older individuals experience reduced renal function by virtue of their advanced age, care should be taken
in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT
interval. Therefore, precaution should be taken when using CIPRO with concomitant drugs that
can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in
patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected
hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1% of orally
treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients
are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in
extremities, injection site reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis,
phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression,
paresthesia, abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain,
flare up of gout
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary
retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
hemoptysis, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity/
phototoxicity reaction, flushing, fever, chills, angioedema, edema of the face, neck, lips,
conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum,
sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception,
overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad
taste, chromatopsia
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be
related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
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pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment.
An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of
overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin
cannot be excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
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interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these events are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening
anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure
(including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension
(postural), jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis
(oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity
reaction, potassium elevation (serum), prothrombin time prolongation or decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like
reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes,
toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also
INHALATIONAL ANTHRAXADDITIONAL INFORMATION.)
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
regard to drug relationship are listed below:
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
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(0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%),
elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
observed and given supportive treatment, including monitoring of renal function and administration of
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
is removed from the body after hemodialysis or peritoneal dialysis.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats,
and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral
doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs
observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed
in these animals, occurring 10-14 days after dosing.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the Dosage
Guidelines table.
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s
host-defense mechanisms, and the status of renal function and hepatic function.
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
however, for severe and complicated infections more prolonged therapy may be required.
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
solution, other highly buffered drugs, or other products containing calcium, iron or zinc.
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ADULT DOSAGE GUIDELINES
Infection
Severity
Dose
Frequency Usual Durations†
Urinary Tract
Acute Uncomplicated
250 mg
q 12 h
3 days
Mild/Moderate
250 mg
q 12 h
7 to 14 days
Severe/Complicated
500 mg
q 12 h
7 to 14 days
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 days
Prostatitis
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 days
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 days
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 days
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 days
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
Gonococcal Infections
Inhalational anthrax
500 mg
q 12 h
60 days
(post-exposure)**
* used in conjunction with metronidazole
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have
disappeared, except for inhalational anthrax (post-exposure).
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely
to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the
physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens).
Equivalent AUC Dosing Regimens
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
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Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended, particularly for patients with severe renal dysfunction. The following table provides
dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dose
> 50
See Usual Dosage.
30 – 50
250 – 500 mg q 12 h
5 – 29
250 – 500 mg q 18 h
Patients on hemodialysis
250 – 500 mg q 24 h (after dialysis)
or Peritoneal dialysis
When only the serum creatinine concentration is known, the following formula may be used to estimate
creatinine clearance.
Men: Creatinine clearance (mL/min) =
Weight (kg) x (140 - age)
72 x serum creatinine (mg/dL)
Women: 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered
at the intervals noted above. Patients should be carefully monitored.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
Guidelines table. An increased incidence of adverse events compared to controls, including
events related to joints and/or surrounding tissues, has been observed. (See ADVERSE
REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
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PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
HOW SUPPLIED
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
tablets containing 250 mg ciprofloxacin. The 250 mg tablet is coded with the word “BAYER” on one
side and “CIP 250” on the reverse side. CIPRO is also available as capsule shaped, slightly yellowish
film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet is coded with the
word “BAYER” on one side and “CIP 500” on the reverse side. The 750 mg tablet is coded with the
word “BAYER” on one side and “CIP 750” on the reverse side. CIPRO 250 mg, 500 mg, and 750 mg
are available in bottles of 50, 100, and Unit Dose packages of 100.
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Bottles of 50:
Strength
750 mg
NDC Code
NDC 0085-1756-01
Tablet Identification
CIPRO 750
Bottles of 100:
250 mg
NDC 0085-1758-01
CIPRO 250
500 mg
NDC 0085-1754-01
CIPRO 500
Unit Dose
Package of 100:
250 mg
NDC 0085-1758-02
CIPRO 250
500 mg
NDC 0085-1754-02
CIPRO 500
750 mg
NDC 0085-1756-02
CIPRO 750
Store below 30°C (86°F).
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
pharmacist. See Instructions To The Pharmacist For Use/Handling.
Total volume
Ciprofloxacin
Ciprofloxacin
Strengths after reconstitution
Concentration
contents per bottle
NDC Code
5%
100 mL
250 mg/5 mL
5,000 mg
0085-1777-01
10%
100 mL
500 mg/5 mL
10,000 mg
0085-1773-01
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
teaspoon is provided for the patient.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in
juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal.
In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by
histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times
the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This
dose was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release, since they are
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
produces hypotension but the effect in this species is inconsistent and less pronounced.
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In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days
Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by
Patient at 5 to 9 Days
Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new
infections.
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INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL.6 Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day drug administration period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
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Usa
ge Illustration
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
which must be combined prior to dispensing.
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of ciprofloxacin.
Appropriate Dosing Volumes of the Oral Suspensions:
Dose
5%
10%
250 mg
5 mL
2.5 mL
500 mg
10 mL
5 mL
750 mg
15 mL
7.5 mL
Preparation of the suspension:
1. The small bottle
Usa
ge Illustration
2. Open both bottles.
contains the
Child-proof cap: Press
microcapsules, the
down according to
large bottle
instructions on the cap
contains the
while turning to the
diluent.
left.
3. Pour the
4. Remove the top layer
microcapsules
of the diluent bottle
completely into the
label (to reveal the
larger bottle of
CIPRO Oral
diluent. Do not add
Suspension label).
water to the
Close the large bottle
suspension.
completely according
to the directions on the
cap and shake
vigorously for about
15 seconds. The
suspension is ready for
use.
CIPRO Oral Suspension should not be administered through feeding tubes due to its
physical characteristics.
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
approximately 15 seconds and not to chew the microcapsules.
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References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline.,
CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
3. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard NCCLS
Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s
Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA,
CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening
Illnesses). 6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J
Infect Dis 1993; 167:1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS).
Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6):1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone
exposure. Evaluation of a case registry of the European network of teratology information services
(ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
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MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place
of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO can cause side effects
that may be serious or even cause death. If you get any of the following serious side effects, get
medical help right away. Talk with your healthcare provider about whether you should
continue to take CIPRO.
• Tendon rupture or swelling of the tendon (tendinitis)
• Tendons are tough cords of tissue that connect muscles to bones.
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take
fluoroquinolone antibiotics, including CIPRO. The risk of getting tendon problems is
higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in
patients who take fluoroquinolones who do not have the above risk factors.
• Other reasons for tendon ruptures can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or
inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by
your healthcare provider. Avoid exercise and using the affected area. The most common
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area of pain and swelling is the Achilles tendon at the back of your ankle. This can also
happen with other tendons. Talk to your healthcare provider about the risk of tendon
rupture with continued use of CIPRO. You may need a different antibiotic that is not a
fluoroquinolone to treat your infection.
• Tendon rupture can happen while you are taking or after you have finished taking CIPRO.
Tendon ruptures have happened up to several months after patients have finished taking their
fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a tendon
rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
• See the section “What are the possible side effects of CIPRO?” for more information
about side effects.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain
germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon
(musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be
used as the first choice of antibiotic medicine in children under 18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children under
18 years old, except to treat specific serious infections, such as complicated urinary tract
infections and to prevent anthrax disease after breathing the anthrax bacteria germ (inhalational
exposure). It is not known if CIPRO XR is safe and works in children under 18 years of age.
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral
infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including
CIPRO, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are
taking CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
• have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are
allergic to any of the ingredients in CIPRO. Ask your healthcare provider if you are not sure.
See the list of ingredients in CIPRO at the end of this Medication Guide.
• also take a medicine called tizanidine (Zanaflex®). Serious side effects from tizanidine are
likely to happen.
What should I tell my healthcare provider before taking CIPRO?
See “What is the most important information I should know about CIPRO?”
Tell your healthcare provider about all your medical conditions, including if
you:
• have tendon problems
• have central nervous system problems (such as epilepsy)
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• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work
well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your
unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other
medicines can affect each other causing side effects. Especially tell your healthcare provider if
you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain
relief are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones
may increase your risk of central nervous system effects and seizures. See "What are the
possible side effects of CIPRO?".
• a blood thinner (warfarin, Coumadin®, Jantoven®)
• tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine. See
“Who should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible side
effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended Phenytoin
Sodium®, Prompt Penytoin Sodium®, Phenytek®)
• products that contain caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the
possible side effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance
of tendon injury. See “What is the most important information I should know about
CIPRO?”
• methotrexate (Trexall®)
• Probenecid (Probalan®, Col-probenecid®)
• Metoclopromide (Reglan®, Reglan ODT®)
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from working
correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after
taking these products:
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• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum,
iron, or zinc
• sucralfate (Carafate®)
• didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you
can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day.
Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to
make sure the suspension is mixed well. Close the bottle completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet
whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified
juices alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you
finish your prescribed treatment, unless:
• you have tendon effects (see “What is the most important information I should
know about CIPRO?”),
• you have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
• your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic
medicines may not work in the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember.
Do not take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than
one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
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If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO
I.V. after being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance of getting
anthrax disease or worsening of the disease after you are exposed to the anthrax bacteria
germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking CIPRO
without talking with your healthcare provider. If you stop taking CIPRO too soon, it may
not keep you from getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or I.V.
When taking your CIPRO to prevent anthrax infection, you and your healthcare provider
should talk about whether the risks of stopping CIPRO too soon are more important than
the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets, Oral
Suspension or I.V. for anthrax are more important than the risks.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do
other activities that require mental alertness or coordination until you know how CIPRO
affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make your
skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds.
You could get severe sunburn, blisters or swelling of your skin. If you get any of these
symptoms while taking CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the
most important information I should know about CIPRO?”
Other serious side effects of CIPRO include:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics including
CIPRO. Tell your healthcare provider if you have a history of seizures. Ask your healthcare
provider whether taking CIPRO will change your risk of having a seizure.
Central Nervous System (CNS) side effects may happen as soon as after taking the first
dose of CIPRO. Talk to your healthcare provider right away if you get any of these side
effects, or other changes in mood or behavior:
• feel dizzy
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
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• trouble sleeping
• nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even
after only one dose. Stop taking CIPRO and get emergency medical help right away if you
get any of the following symptoms of a severe allergic reaction:
• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right
away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a
sign of a more serious reaction to CIPRO.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or
irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as
prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be
very dangerous. The chances of this event are higher in people:
• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or
bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can
happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Talk with your healthcare provider right away if you
get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or
feet:
• pain
• burning
• tingling
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• numbness
• weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes
medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar
(hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low
blood sugar with CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18
years old. Tell your child’s healthcare provider if your child has any joint problems during
or after treatment with CIPRO.
The most common side effects of CIPRO include:
• nausea
• headache
• diarrhea
• vomiting
• vaginal yeast infection
• changes in liver function tests
• pain or discomfort in the abdomen
These are not all the possible side effects of CIPRO. Tell your healthcare provider about any side
effect that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely
thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would
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like more information about CIPRO, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about CIPRO that is written for healthcare
professionals. For more information go to www.CIPRO.com or call 1-800-526-4099.
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene
glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20. Diluentmedium-chain triglycerides, sucrose,
lecithin, water, and strawberry flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
Revised October 2008
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Company logo
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
Company logo
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
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Corporation.
Rx Only
81532304, R.1
02/09
Bay o 9867
5202-2-A-U.S.-26
©2009 Bayer HealthCare Pharmaceuticals Inc.
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
81532266, R.1
02/09
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis
and tendon rupture in all ages. This risk is further increased in older patients usually over 60
years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or
lung transplants (See WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3and its chemical structure is: Chemcial Structure
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
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Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q12h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg
administered intravenously. Comparison of the pharmacokinetic parameters following the 1st
and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no
substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin
given over 60 minutes every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every
12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8
hours has been shown to produce an AUC at steady-state equivalent to that produced by a
750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that
observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours
produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
AUC (µg•hr/mL)
Cmax (µg/mL)
500 mg
q12h, P.O.
13.7 a
2.97
400 mg
q12h, I.V.
12.7 a
4.56
750 mg
q12h, P.O.
31.6 b
3.59
400 mg
q8h, I.V.
32.9 c
4.07
a AUC0-12h
bAUC 24h=AUC0-12h × 2
cAUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial
secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It
has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug
diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak
serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are
lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human
urine which together account for approximately 10% of the intravenous dose. The binding of
ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin
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with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations
of these drugs and could lead to clinically significant adverse events of the coadministered drug
(see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35
L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in
the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually
exceed 200 µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours
after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL
0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The
renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually
complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum
concentrations after intravenous dosing, only a small amount of the administered dose (< 1%)
is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered
from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in
patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
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PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
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Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
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technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
C. jejunib
ATCC 33560
0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeaec
ATCC 49226
0.001-0.008
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
b C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller
Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37oC for
48 hours and for 42oC at 24 hours2, respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1%
defined growth supplement in a 5% CO2 environment at 35-37oC for 20-24 hours3.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with
a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)3.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
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a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)3.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus
pneumoniae, or Moraxella catarrhalis.
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Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.5
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy
with CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are
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associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse
reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may
require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand,
the biceps, the thumb, and other tendon sites have also been reported. The risk of developing
fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants. Factors, in addition to age and corticosteroid use, that may
independently increase the risk of tendon rupture include strenuous physical activity, renal
failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon
rupture have also occurred in patients taking fluoroquinolones who do not have the above risk
factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be
discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon.
Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact
their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline,
methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and
could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
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CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to
uncertain etiology, have been reported rarely in patients receiving therapy with quinolones,
including ciprofloxacin. These events may be severe and generally occur following the
administration of multiple doses. Clinical manifestations may include one or more of the
following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or
any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CIPRO, and may range in
severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after
the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
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including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions,
the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema,
exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V”
area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with
the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these
sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs
(See ADVERSE REACTIONS/ Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
•to contact their healthcare provider if they experience pain, swelling, or inflammation of a
tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and
discontinue CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones
is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs,
and in patients with kidney, heart or lung transplants.
•that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or
not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by CIPRO I.V. or other antibacterial drugs in the future.
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•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
•that photosensitivity/phototoxicity has been reported in patients receiving quinolones.
Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or
UVA/B treatment) while taking quinolones. If patients need to be outdoors while using
quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and
discuss other sun protection measures with their physician. If a sunburn-like reaction or skin
eruption occurs, patients should contact their physician.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
•that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
•that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
•that diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can
develop watery and bloody stools (with or without stomach cramps and fever) even as late as
two or more months after having taken the last dose of the antibiotic. If this occurs, patients
should contact their physician as soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments
made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
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The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems
gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
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treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but
the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.8,9 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for
less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in
pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless
the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6
and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose
levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic
dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an
increased incidence of abortion, but no teratogenicity was observed at either dose level. After
intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no
embryotoxicity or teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
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PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure),
see DOSAGE
AND
ADMINISTRATION and INHALATIONAL
ANTHRAX
–
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including those related to joints and/or surrounding tissues. The rates
of these events in pediatric patients with complicated urinary tract infection and pyelonephritis
within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents.
The rates of these events occurring at any time up to the one year follow-up were 13.7%
(46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug
relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of
age were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders
including tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This
risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or
tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur
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during or after completion of therapy; cases occurring up to several months after
fluoroquinolone treatment have been reported. Caution should be used when prescribing
CIPRO I.V. to elderly patients especially those on corticosteroids. Patients should be informed
of this potential side effect and advised to discontinue CIPRO I.V. and contact their healthcare
provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning,
WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin
encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or
equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall
differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy
cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the
risk of adverse reactions may be greater in patients with impaired renal function. No alteration
of dosage is necessary for patients greater than 65 years of age with normal renal function.
However, since some older individuals experience reduced renal function by virtue of their
advanced age, care should be taken in dose selection for elderly patients, and renal function
monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported
were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V.
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as
local skin reactions which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
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CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
hypertension,
hypotension,
angina
pectoris,
atrial
flutter,
ventricular
ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions
including
life-threatening anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative
dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae,
hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning,
paresthesia, erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
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and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
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In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure. Decisions to include
these events in labeling are typically based on one or more of the following factors: (1) seriousness
of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative
dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia,
hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia,
moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity
reaction, potassium elevation (serum), prothrombin time prolongation or decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like
reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes,
toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also
INHALATIONAL ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
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Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a
larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation
of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
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Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax (post-exposure) is
60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table
below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the
liver and through the intestine. These alternative pathways of drug elimination appear to
compensate for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended for patients with severe renal dysfunction. The
following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
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72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased
incidence of adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
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dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of
1–2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Hospira,
Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Baxter
Healthcare Corporation, Deerfield, IL 60015.
Bayer Response I.V. 12 Feb 2009.doc
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mL 5% Dextrose
200 mg, 0.2%
400 mg, 0.2%
0085-1781-01
0085-1762-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
Bayer Response I.V. 12 Feb 2009.doc
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500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean
peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects
on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In
the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean
steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL.6
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin
beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group
(9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the
30-day drug administration period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Bayer Response I.V. 12 Feb 2009.doc
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Bayer Response I.V. 12 Feb 2009.doc
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline.,
CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
3. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS
Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products
Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA,
CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening
Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during
prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J
Infect Dis 1993; 167: 1239-42.
Bayer Response I.V. 12 Feb 2009.doc
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS).
Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone
exposure. Evaluation of a case registry of the European network of teratology information
services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
Bayer Response I.V. 12 Feb 2009.doc
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:07.989920
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s69,19847s43,19857s50,20780s27lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 43}
|
11,775
|
structural formula
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
07/11
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
Reference ID: 3030756
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
2
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
3
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Reference ID: 3030756
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate (I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
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report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
provide the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
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E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
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related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
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and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure (including
pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones,
including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including:
dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin,
the drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones,
ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may
predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or
in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g.
certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients,
Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
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Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
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PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
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• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
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Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
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exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
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Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
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involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
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hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
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An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
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Reference ID: 3030756
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seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
Reference ID: 3030756
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OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
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For current labeling information, please visit https://www.fda.gov/drugsatfda
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
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Reference ID: 3030756
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
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Reference ID: 3030756
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available in a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in a 400 mg strength. The premixed solution is supplied in latex-free flexible containers as
follows:
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
200 mL 5% Dextrose
400 mg, 0.2%
50419-759-01
STORAGE
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
23
Reference ID: 3030756
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
24
Reference ID: 3030756
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Reference ID: 3030756
25
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
26
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial
Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000.
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
6. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
8. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
Reference ID: 3030756
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is: structural formula
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
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For current labeling information, please visit https://www.fda.gov/drugsatfda
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MICROBIOLOGY
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair,
and recombination.
Drug Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin and other fluoroquinolones. There
is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro
resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due
to spontaneous mutations occurs in vitro at a general frequency of between < 10-9 to 1x10-6.
Activity in vitro and in vivo
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not
exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Reference ID: 3000237
NDA 019857 Cipro IV Microbiology Update 06 July 2011
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following in vitro data are available, but their clinical significance is unknown. Ciprofloxacin
exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥ 90%)
strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin
intravenous formulations in treating clinical infections due to these microorganisms have not been
established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
• Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of
bacteria to antimicrobial compounds. The MICs should be determined using a standardized
procedure. Standardized procedures are based on a dilution method1 (broth or agar) or
equivalent with standardized inoculum concentrations and standardized concentrations of
ciprofloxacin powder. The MIC values should be interpreted according to the criteria
outlined in Table 1.
• Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of
microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a
5-µg ciprofloxacin disk should be interpreted according to the criteria outlined in Table 1.
Interpretation involves correlation of the diameter obtained in the disk test with the MIC for
ciprofloxacin.
Reference ID: 3000237
NDA 019857 Cipro IV Microbiology Update 06 July 2011
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1: Susceptibility Interpretive Criteria for Ciprofloxacin
MIC (μg/mL)
Zone Diameter (mm)
Species
S
I
R
S
I
R
Enterobacteriacae
≤1
2
≥4
≥21
16-20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16-20
≤15
Methicillin susceptible
Staphylococcus species
≤1
2
≥4
≥21
16-20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16-20
≤15
Haemophilus influenzae
≤1a
e
e
≥21b
e
e
Haemophilus parainfluenzae
≤1a
e
e
≥21b
e
e
Penicillin susceptible
Streptococcus pneumoniae
≤1c
2c
≥4c
≥21d
16-20d
≤15d
Streptococcus pyogenes
≤1c
2c
≥4c
≥21d
16-20d
≤15d
S=susceptible, I=Intermediate, and R=resistant.
a This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)1 .
b This zone diameter standard is applicable only to tests with Haemophilus influenzae using Haemophilus Test
Medium (HTM)3 .
c These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
dThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar
supplemented with 5% sheep blood incubated in 5% CO2.
eThe current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding
zone diameter results suggestive of a “Non-Susceptible” category should be submitted to a reference laboratory for
further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
• Quality Control: Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures. For dilution
technique, standard ciprofloxacin powder should provide the following MIC values: standard
ciprofloxacin powder should give the MIC values provided in Table 2. For diffusion technique, the
5-µg ciprofloxacin disk should provide the zone diameters outlined in Table 2.
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Table 2: Quality Control for Susceptibility Testing
Strains
MIC range (μg/mL)
Zone Diameter
(mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03a
34–42b
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC29213
0.12–0.5
-
Staphylococcus aureus ATCC25923
-
22–30
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1 .
b These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus
Test Medium (HTM)3 .
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
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aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
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Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If
these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and
appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in
patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction).
(See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
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fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
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Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
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Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
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malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.8,9 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
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fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
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SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with flouroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
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decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
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Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
7-14 Days
7-14 Days
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
≥ 4-6 Weeks
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
28 Days
Empirical Therapy
in
Severe
Febrile Neutropenic
Patients
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
Not to exceed
q8h
q4h
7-14 Days
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
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750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
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(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
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5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V.
is available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Hospira, Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Baxter Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1759-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1782-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
Reference ID: 3000237
NDA 019857 Cipro IV Microbiology Update 06 July 2011
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL6. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests
for Bacteria That Grow Aerobically; Approved Standard – Eighth Edition. CLSI Document M7-A8,
Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009.
2. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second
Edition. CLSI Document M45-A2, CLSI, Wayne, PA, January, 2010.
3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk
Susceptibility Tests; Approved Standard – Tenth Edition. CLSI Document M2-A10, Vol. 29, No. 1,
CLSI, Wayne, PA, January, 2009.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
READ THE MEDICATION GUIDE THAT COMES WITH CIPRO® BEFORE YOU START TAKING IT AND EACH
TIME YOU GET A REFILL. THERE MAY BE NEW INFORMATION. THIS MEDICATION GUIDE DOES NOT TAKE
THE PLACE OF TALKING TO YOUR HEALTHCARE PROVIDER ABOUT YOUR MEDICAL CONDITION OR YOUR
TREATMENT.
What is the most important information I should know about CIPRO?
CIPRO BELONGS TO A CLASS OF ANTIBIOTICS CALLED FLUOROQUINOLONES. CIPRO CAN CAUSE SIDE
EFFECTS THAT MAY BE SERIOUS OR EVEN CAUSE DEATH. IF YOU GET ANY OF THE FOLLOWING
SERIOUS SIDE EFFECTS, GET MEDICAL HELP RIGHT AWAY. TALK WITH YOUR HEALTHCARE PROVIDER
ABOUT WHETHER YOU SHOULD CONTINUE TO TAKE CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis)
• Tendon problems can happen in people of all ages who take CIPRO. Tendons are
tough cords of tissue that connect muscles to bones. Symptoms of tendon problems
may include:
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
•
The risk of getting tendon problems while you take CIPRO is higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO. Other reasons that can increase your risk of
tendon problems can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or
inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by
your healthcare provider. Avoid exercise and using the affected area. The most common
area of pain and swelling is the Achilles tendon at the back of your ankle. This can also
happen with other tendons.
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Talk to your healthcare provider about the risk of tendon rupture with continued use
of CIPRO. You may need a different antibiotic that is not a fluoroquinolone to treat your
infection.
• Tendon rupture can happen while you are taking or after you have finished taking
CIPRO. Tendon ruptures have happened up to several months after patients have
finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a
tendon rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
2. WORSENING OF MYASTHENIA GRAVIS (A DISEASE WHICH CAUSES MUSCLE WEAKNESS).
FLUOROQUINOLONES LIKE CIPRO MAY CAUSE WORSENING OF MYASTHENIA GRAVIS SYMPTOMS,
INCLUDING MUSCLE WEAKNESS AND BREATHING PROBLEMS. CALL YOUR HEALTHCARE PROVIDER
RIGHT AWAY IF YOU HAVE ANY WORSENING MUSCLE WEAKNESS OR BREATHING PROBLEMS.
SEE THE SECTION “WHAT ARE THE POSSIBLE SIDE EFFECTS OF CIPRO?” FOR MORE INFORMATION
ABOUT SIDE EFFECTS.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused
by certain germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or
tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO.
CIPRO should not be used as the first choice of antibiotic medicine in children under 18
years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children
under 18 years old, except to treat specific serious infections, such as complicated
urinary tract infections and to prevent anthrax disease after breathing the anthrax
bacteria germ (inhalational exposure). It is not known if CIPRO XR is safe and works in
children under 18 years of age.
SOMETIMES INFECTIONS ARE CAUSED BY VIRUSES RATHER THAN BY BACTERIA. EXAMPLES INCLUDE
VIRAL INFECTIONS IN THE SINUSES AND LUNGS, SUCH AS THE COMMON COLD OR FLU. ANTIBIOTICS,
INCLUDING CIPRO, DO NOT KILL VIRUSES.
CALL YOUR HEALTHCARE PROVIDER IF YOU THINK YOUR CONDITION IS NOT GETTING BETTER WHILE
YOU ARE TAKING CIPRO.
Who should not take CIPRO?
DO NOT TAKE CIPRO IF YOU:
•
HAVE EVER HAD A SEVERE ALLERGIC REACTION TO AN ANTIBIOTIC KNOWN AS A
FLUOROQUINOLONE, OR ARE ALLERGIC TO ANY OF THE INGREDIENTS IN CIPRO. ASK YOUR
HEALTHCARE PROVIDER IF YOU ARE NOT SURE. SEE THE LIST OF INGREDIENTS IN CIPRO AT THE
END OF THIS MEDICATION GUIDE.
•
ALSO TAKE A MEDICINE CALLED TIZANIDINE (ZANAFLEX®). SERIOUS SIDE EFFECTS FROM
TIZANIDINE ARE LIKELY TO HAPPEN.
What should I tell my healthcare provider before taking CIPRO?
SEE “WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT CIPRO?”
Tell your healthcare provider about all your medical conditions, including if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis) have central nervous
system problems (such as epilepsy)
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work
well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your
unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other
medicines can affect each other causing side effects. Especially tell your healthcare provider if
you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief
are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may
increase your risk of central nervous system effects and seizures. See "What are the
possible side effects of CIPRO?"
• a blood thinner (warfarin, Coumadin®, Jantoven®)
•
tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine.
See “Who should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
•
glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible
side effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium
®, Dilantin-125®, Dilantin®, Extended
Phenytoin Sodium
, Cerebyx
®
®, Phenytek )
• products that contain
, Prompt Penyto
®
in Sodium
caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the
possible side effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance
of tendon injury. See “What is the most important information I should know about
CIPRO?”
•
methotrexate (Trexall®
•
Probenecid (Probalan®, Col-probenecid®
•
Metoclopromide (Reglan®
)
• Certain medicines may keep
,
)
Reglan ODT
CIPRO Tablet
)
s
®
, CIPRO Oral Suspension from working
correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after
taking these products:
• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron,
or zinc
•
sucralfate (Carafate®)
•
didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are
listed above.
KNOW THE MEDICINES YOU TAKE. KEEP A LIST OF YOUR MEDICINES AND SHOW IT TO YOUR
HEALTHCARE PROVIDER AND PHARMACIST WHEN YOU GET A NEW MEDICINE.
Reference ID: 3000237
®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you
can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day.
Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to
make sure the suspension is mixed well. Close the bottle completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet
whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you finish
your prescribed treatment, unless:
•
you have tendon effects (see “What is the most important information I should
know about CIPRO?”),
•
you have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
•
your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic
medicines may not work in the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember.
Do not take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than
one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V.
after being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance
of getting anthrax disease or worsening of the disease after you are exposed to the
anthrax bacteria germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking
CIPRO without talking with your healthcare provider. If you stop taking CIPRO too
soon, it may not keep you from getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or
I.V. When taking your CIPRO to prevent anthrax infection, you and your healthcare
provider should talk about whether the risks of stopping CIPRO too soon are more
important than the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets, Oral
Suspension or I.V. for anthrax are more important than the risks.
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do
other activities that require mental alertness or coordination until you know how CIPRO
affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make
your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning
beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these
symptoms while taking CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the
most important information I should know about CIPRO?”
OTHER SERIOUS SIDE EFFECTS OF CIPRO INCLUDE:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics
including CIPRO. Tell your healthcare provider if you have a history of seizures. Ask
your healthcare provider whether taking CIPRO will change your risk of having a
seizure.
CENTRAL NERVOUS SYSTEM (CNS) SIDE EFFECTS MAY HAPPEN AS SOON AS AFTER TAKING THE
FIRST DOSE OF CIPRO. TALK TO YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU GET ANY OF
THESE SIDE EFFECTS, OR OTHER CHANGES IN MOOD OR BEHAVIOR:
• feel dizzy
•
seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
•
tremors
• feel anxious or nervous
•
confusion
•
depression
• trouble sleeping
•
nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even
after only one dose. Stop taking CIPRO and get emergency medical help right away if you
get any of the following symptoms of a severe allergic reaction:
•
hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
•
faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right
away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a
sign of a more serious reaction to CIPRO.
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or
irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as
prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be
very dangerous. The chances of this event are higher in people:
• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or
bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can
happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Talk with your healthcare provider right away if you get
any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
•
pain
•
burning
•
tingling
•
numbness
•
weakness
CIPRO MAY NEED TO BE STOPPED TO PREVENT PERMANENT NERVE DAMAGE.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes
medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar
(hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get
low blood sugar with CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18
years old. Tell your child’s healthcare provider if your child has any joint problems during or
after treatment with CIPRO.
THE MOST COMMON SIDE EFFECTS OF CIPRO INCLUDE:
•
nausea
•
headache
•
diarrhea
•
vomiting
• vaginal yeast infection
• changes in liver function tests
•
pain or discomfort in the abdomen
THESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF CIPRO. TELL YOUR HEALTHCARE PROVIDER
ABOUT ANY SIDE EFFECT THAT BOTHERS YOU, OR THAT DOES NOT GO AWAY.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO
FDA AT 1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely
thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
KEEP CIPRO AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.
General Information about CIPRO
MEDICINES ARE SOMETIMES PRESCRIBED FOR PURPOSES OTHER THAN THOSE LISTED IN A
MEDICATION GUIDE. DO NOT USE CIPRO FOR A CONDITION FOR WHICH IT IS NOT PRESCRIBED. DO
NOT GIVE CIPRO TO OTHER PEOPLE, EVEN IF THEY HAVE THE SAME SYMPTOMS THAT YOU HAVE. IT
MAY HARM THEM.
THIS MEDICATION GUIDE SUMMARIZES THE MOST IMPORTANT INFORMATION ABOUT CIPRO. IF YOU
WOULD LIKE MORE INFORMATION ABOUT CIPRO, TALK WITH YOUR HEALTHCARE PROVIDER. YOU CAN
ASK YOUR HEALTHCARE PROVIDER OR PHARMACIST FOR INFORMATION ABOUT CIPRO THAT IS
WRITTEN FOR HEALTHCARE PROFESSIONALS. FOR MORE INFORMATION CALL 1-888-84 BAYER (1-888
842-2937).
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone,
magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following
compositions:
Microcapsulesciprofloxacin,
povidone,
methacrylic
acid
copolymer,
hypromellose,
magnesium
stearate,
and
Polysorbate
20.
Diluentmedium-chain triglycerides, sucrose, lecithin, water, and strawberry
flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
Revised June 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
06/11
©2011 Bayer HealthCare Pharmaceuticals Inc.
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:08.084638
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019847s050,019857s057lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 50}
|
11,776
|
------------------------------ DRUG INTERACTIONS ----------------------------
Interacting Drug
Interaction
Serious and fatal reactions. Avoid concomitant
Theophylline
use. M
onitor serum level (7)
Anticoagulant effect enhanced. Monitor
Warfarin
prothrombin time, INR, and bleeding 7)
Hypoglycemia including fatal outcomes have
Antidiabetic agents
been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
May increase serum creatinine. Monitor serum
Cyclosporine
creatinine (7)
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
See full prescribing information for pediatric patients (8.4) and use in
geriatric (8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 2/2015
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CIPRO
IV® safely and effectively. See full prescribing information for CIPRO IV.
CIPRO IV (ciprofloxacin) injection, for intravenous use
Initial U.S. Approval: 1990
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
See full prescribing information for complete boxed warning.
•
Fluoroquinolones, including CIPRO IV®, are associated with an
increased risk of tendinitis and tendon rupture in all ages. This
risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants [see Warnings and Precautions
(5.1)].
•
Fluoroquinolones, including CIPRO IV, may exacerbate muscle
weakness in persons with myasthenia gravis. Avoid CIPRO IV in
patients with known history of myasthenia gravis [see Warnings
and Precautions (5.2)].
-------------------------- RECENT MAJOR CHANGES -------------------------
Indications and Usage, Plague (1.12)
MM/2014
Dosage and Administration, Adults (2.1), Pediatrics (2.2)
MM/2014
--------------------------- INDICATIONS AND USAGE -------------------------
CIPRO IV is a fluoroquinolone antibacterial indicated in adults (≥18 years of
age) with infections caused by designated, susceptible bacteria and in
pediatric patients where indicated.
•
Urinary tract infections in adults (1.1)
•
Lower respiratory tract infections in adults (1.2)
•
Nosocomial Pneumonia (1.3)
•
Skin and skin structure infections in adults (1.4)
•
Bone and joint infections in adults (1.5)
•
Complicated intra-abdominal infections in adults (1.6)
•
Acute sinusitis in adults (1.7)
•
Chronic bacterial prostatitis in adults (1.8)
•
Empirical therapy for febrile neutropenic patients (1.9)
•
Complicated urinary tract infections and pyelonephritis in pediatric
patients (1.10)
•
Inhalational anthrax postexposure in adult and pediatric patients (1.11)
•
Plague in adult and pediatric patients (1.12)
•
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV
should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria. (1.14)
---------------------- DOSAGE AND ADMINISTRATION ---------------------
Adult Dosage Guidelines
Infection
Dose
Frequency
Duration
Urinary Tract
200 to 400 mg
every 12 to 8 hours
7–14 days
Lower Respiratory Tract
400 mg
every 12 to 8 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Skin and Skin Structure
400 mg
every 12 to 8 hours
7–14 days
Bone and Joint
400 mg
every 12 to 8 hours 4 to 8 weeks
Intra-Abdominal
400 mg
every 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
Chronic Bacterial
prostatitis
400 mg
every 12 hours
28 days
Empirical Therapy In
Febrile Neutropenic
Patients
400 mg
and
every 8 hours
Piperacillin
50 mg/kg
every 4 hours
7–14 days
Inhalational
anthrax(post-exposure)
400 mg
every 12 hours
60 days
Plague
400 mg
every 12 to 8 hours
14 days
Pediatric Intravenous Dosing Guidelines
Infection
Dose
Frequency
Duration
Complicated Urinary
Tract or Pyelonephritis
(patients from 1 to 17
years of age)
6 mg/kg to 10 mg/kg
(maximum 400 mg
per dose)
Every 8
hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)
10 mg/kg
(maximum 400 mg
per dose)
Every 12
hours
60 days
Plague
10 mg/kg
(maximum 400 mg
per dose)
Every 12
to 8 hours
10–21 days
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
•
Injection: 400 mg/200 mL
------------------------------ CONTRAINDICATIONS ----------------------------
•
Known sensitivity to CIPRO or other quinolones (4.1, 5.3)
•
Concomitant administration with tizanidine (4.2)
----------------------- WARNINGS AND PRECAUTIONS ---------------------
•
Hypersensitivity and other serious reactions: Serious and sometimes
fatal reactions may occur after first or subsequent doses. Discontinue at
first sign of skin rash, jaundice or any sign of hypersensitivity. (4.1, 5.3,
5.4)
•
Hepatotoxicity: Discontinue immediately if signs and symptoms of
hepatitis occur. (5.5)
•
Central nervous system effects, including convulsions, increased
intracranial pressure (pseudotumor cerebri) and toxic psychosis have
been reported. Caution should be taken in patients predisposed to
seizures. (5.7)
•
Clostridium difficile-associated diarrhea: Evaluate if colitis occurs. (5.8)
•
Peripheral neuropathy: Discontinue if symptoms occur in order to
prevent irreversibility. (5.9)
•
QT Prolongation: Prolongation of the QT interval and isolated cases of
torsade de pointes have been reported. Avoid use in patients with known
prolongation, those with hypokalemia, and with other drugs that prolong
the QT interval. (5.10, 7, 8.5)
------------------------------ ADVERSE REACTIONS ----------------------------
The most common adverse reactions ≥1% were nausea, diarrhea, liver
function tests abnormal, vomiting, central nervous system disturbance, local
intravenous site reactions eosinophilia, headache, restlessness, and rash. (6)
TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT
BAYER HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1
800-FDA-1088 or www.fda.gov/medwatch.
•
Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h
Reference ID: 3695262
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS
WARNING: TENDON EFFECTS AND MYASTHENIA GRAVIS
1 INDICATIONS AND USAGE
1.1 Urinary Tract Infections
1.2 Lower Respiratory Tract Infections
1.3 Nosocomial Pneumonia
1.4 Skin and Skin Structure Infections
1.5 Bone and Joint Infections
1.6 Complicated Intra-Abdominal Infections
1.7 Acute Sinusitis
1.8 Chronic Bacterial Prostatitis
1.9 Empirical Therapy for Febrile Neutropenic Patients
1.10 Complicated Urinary Tract Infections and Pyelonephritis
1.11 Inhalational Anthrax (post-exposure)
1.12 Plague
1.13 Limitations of Use
1.14 Usage
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in Adults
2.2 Dosage in Pediatric Patients
2.3 Preparation of CIPRO IV for Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Hypersensitivity
4.2 Tizanidine
5 WARNINGS AND PRECAUTIONS
5.1 Tendinopathy and Tendon Rupture
5.2 Exacerbation of Myasthenia Gravis
5.3 Hypersensitivity Reactions
5.4 Other Serious and Sometimes Fatal Reactions
5.5 Hepatotoxicity
5.6 Serious Adverse Reactions with Concomitant Theophylline
5.7 Central Nervous System Effects
5.8 Clostridium Difficile-Associated Diarrhea
5.9 Peripheral Neuropathy
5.10 Prolongation of the QT Interval
5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic
Effects in Animals
5.12 Crystalluria
5.13 Photosensitivity/Phototoxicity
5.14 Development of Drug Resistant Bacteria
5.15 Potential Risks With Concomitant Use of Drugs Metabolized by
Cytochrome P450 1A2 Enzymes
5.16 Periodic Assessment of Organ System Functions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Adverse Laboratory Changes
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in
Pediatric Patients
14.3 Inhalational Anthrax in Adults and Pediatrics
14.4 Plague
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
STORAGE
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
Reference ID: 3695262
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
Fluoroquinolones, including CIPRO IV® , are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants
[see Warnings and Precautions (5.1)].
Fluoroquinolones, including CIPRO IV, may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis [see
Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
CIPRO IV is indicated for the treatment of infections caused by susceptible isolates of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration is needed [see Dosage and Administration (2.1, 2.2)].
1.1 Urinary Tract Infections
CIPRO IV is indicated in adult patients for treatment of urinary tract infections caused by Escherichia
coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
rettgeri, Morganella morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa,
methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus
faecalis.
1.2 Lower Respiratory Tract Infections
CIPRO IV is indicated in adult patients for treatment of lower respiratory tract infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae.* Also,
CIPRO IV is indicated for the treatment of acute exacerbations of chronic bronchitis caused by Moraxella
catarrhalis [see Indications and Usage (1.13)].
1.3 Nosocomial Pneumonia
CIPRO IV is indicated in adult patients for treatment of nosocomial pneumonia caused by caused by
Haemophilus influenzae or Klebsiella pneumoniae.
1.4 Skin and Skin Structure Infections
CIPRO IV is indicated in adult patients for treatment of skin and skin structure infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin
susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Reference ID: 3695262
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.5 Bone and Joint Infections
CIPRO IV is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter
cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
1.6 Complicated Intra-Abdominal Infections
CIPRO IV is indicated in adult patients for treatment of complicated intra-abdominal infections (used in
combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
1.7 Acute Sinusitis
CIPRO IV is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus
influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
1.8 Chronic Bacterial Prostatitis
CIPRO IV is indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea
due to Neisseria gonorrhoeae.
1.9 Empirical Therapy for Febrile Neutropenic Patients
CIPRO IV is indicated in adult patients for the treatment of febrile neutropenia in combination with
piperacillin sodium [see Clinical Studies (14.1)].
1.10 Complicated Urinary Tract Infections and Pyelonephritis
CIPRO IV is indicated in pediatric patients one to 17 years of age for treatment of complicated urinary
tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Indications and Usage (1.13), Use
in Specific Populations (8.4), and Clinical Studies (14.2)].
1.11 Inhalational Anthrax (post-exposure)
CIPRO IV is indicated in adults and pediatric patients from birth to 17 years of age for treatment of
inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure
to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely
to predict clinical benefit and provided the initial basis for approval of this indication.1 Supportive clinical
information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax
bioterror attacks of October 2001. [See Clinical Studies (14.3).]
1.12 Plague
CIPRO IV is indicated for treatment of plague, including pneumonic and septicemic plague, due to
Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17
years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for
feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see
Clinical Studies (14.4)].
1.13 Limitation of Use
Use in Pediatric Patients
Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population
Reference ID: 3695262
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
due to an increased incidence of adverse events compared to controls, including events related to joints
and/or surrounding tissues. CIPRO IV, like other fluoroquinolones, is associated with arthropathy and
histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions
(5.11), Adverse Reactions (6.1), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].
Lower Respiratory Tract Infections
CIPRO IV is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to
Streptococcus pneumoniae [see Indications and Usage (1.2)].
1.14 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and
other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are
available, they should be considered in selecting or modifying antibacterial therapy. In the absence of
such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in order
to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO IV may be initiated before results of these tests are known; once results become
available appropriate therapy should be continued. As with other drugs, some isolates of Pseudomonas
aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and
susceptibility testing performed periodically during therapy will provide information not only on the
therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.
2 DOSAGE AND ADMINISTRATION
CIPRO IV should be administered intravenously at dosages described in the appropriate Dosage
Guidelines tables.
2.1 Dosage in Adults
The determination of dosage and duration for any particular patient must take into consideration the
severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the
patient’s host-defense mechanisms, and the status of renal and hepatic function.
Table 1: Adult Dosage Guidelines
Infection1
Dose
Frequency
Usual Duration
Urinary Tract
200 mg to 400 mg
every 12 to every 8 hours
7–14 days
Lower Respiratory Tract
400 mg
every 12 to every 8 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Skin and Skin Structure
400 mg
every 12 to every 8 hours
7–14 days
Bone and Joint
400 mg
every 12 to every 8 hours
4 to 8 weeks
Complicated Intra-Abdominal2
400 mg
every 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
Chronic Bacterial prostatitis
400 mg
every 12 hours
28 days
Empirical Therapy In Febrile
CIPRO IV
every 8 hours
7–14 days
5
Reference ID: 3695262
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Neutropenic Patients
400 mg
and
Inhalational anthrax(post-exposure)3
Plague3
Piperacillin
50 mg/kg
400 mg
400 mg
every 4 hours
every 12 hours
every 12 to 8 hours
60 days
14 days
1.
Due to the designated pathogens (see Indications and Usage.)
2.
Used in conjunction with metronidazole.
3.
Begin administration as soon as possible after suspected or confirmed exposure.
Conversion of Intravenous to Oral Dosing in Adults
Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension
when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology (12.3)].
Table 2: Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO IV Dosage
250 mg Tablet every 12 hours
200 mg intravenous every 12 hours
500 mg Tablet every 12 h
400 mg intravenous every 12 hours
750 mg Tablet every 12 hours
400 mg intravenous every 8 hours
2.2 Dosage in Pediatric Patients
Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by
the severity of the infection.
Table 3: Pediatric Dosage Guidelines
Infection
Dose
(mg/kg)
Frequency
Total Duration
Complicated Urinary Tract or
Pyelonephritis
(patients from 1 to 17 years of age)1
6 mg/kg to 10 mg/kg
(maximum 400 mg per dose; not to
be exceeded even in patients
weighing more than 51 kg)
Every 8 hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)2
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
60 days
Plague2,3
10 mg/kg
(maximum 400 mg per dose)
Every 12 to 8
hours
10–21 days
1.
The total duration of therapy for cUTI and pyelonephritis in the clinical trial was determined by the physician. The mean
duration of treatment was 11 days (range 10 to 21 days).
2.
Begin drug administration as soon as possible after suspected or confirmed exposure.
3.
Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis.
2.3 Dosage Modifications in Patients with Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table
4.
6
Reference ID: 3695262
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal
Function
Creatinine Clearance (mL/min)
Dose
>30
See Usual Dosage.
5–29
200–400 mg every 18–24 hours
When only the serum creatinine concentration is known, the following formulas may be used to estimate
creatinine clearance:
Men - Creatinine clearance (mL/min) = Weight (kg) x (140 – age)
72 x serum creatinine (mg/dL)
Women - 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment and hepatic insufficiency, careful
monitoring is suggested.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric
patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m2).
2.3 Preparation of CIPRO IV for Administration
Flexible Containers
CIPRO IV is available as a 0.2% premixed solution in 5% dextrose in flexible containers of 200 mL. The
solutions in flexible containers do not need to be diluted and may be infused as described above.
2.4 Important Administration Instructions
Intravenous Infusion
CIPRO IV should be administered to by intravenous infusion over a period of 60 minutes. Slow infusion
of a dilute solution into a larger vein will minimize patient discomfort and reduce the risk of venous
irritation.
Hydration of Patients Receiving CIPRO IV
Adequate hydration of patients receiving CIPRO IV should be maintained to prevent the formation of
highly concentrated urine. Crystalluria has been reported with quinolones [see Warnings and Precautions
(5.12), Adverse Reactions (6.1), Nonclinical Toxicology (13.2) and Patient Counseling Information (17)].
3 DOSAGE FORMS AND STRENGTHS
Injection (200 mL in 5% Dextrose, 400 mg, 0.2%) Premix in Flexible Containers, for intravenous
infusion
Reference ID: 3695262
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antibacterials, or any of the product components [see Warnings and
Precautions (5.3)].
4.2 Tizanidine
Concomitant administration with tizanidine is contraindicated [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1 Tendinopathy and Tendon Rupture
Fluoroquinolones, including CIPRO IV, are associated with an increased risk of tendinitis and tendon
rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the
Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the
shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of
developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or
lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the
risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders
such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking
fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can occur,
sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases
occurring up to several months after completion of therapy have been reported. CIPRO IV should be used
with caution in patients with a history of tendon disorders. CIPRO IV should be discontinued if the
patient experiences pain, swelling, inflammation or rupture of a tendon. [See Adverse Reactions (6.2).]
5.2 Exacerbation of Myasthenia Gravis
Fluoroquinolones, including CIPRO IV, have neuromuscular blocking activity and may exacerbate
muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including
deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons
with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis. [See Adverse
Reactions (6.2).]
5.3 Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose,
have been reported in patients receiving quinolone therapy, including CIPRO IV. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema,
dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious
anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation
measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor
amines, and airway management, including intubation, as indicated. [See Adverse Reactions (6.1)].
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5.4 Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported in patients receiving therapy with quinolones, including CIPRO IV. These
events may be severe and generally occur following the administration of multiple doses. Clinical
manifestations may include one or more of the following:
• Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-
Johnson syndrome);
• Vasculitis; arthralgia; myalgia; serum sickness;
• Allergic pneumonitis;
• Interstitial nephritis; acute renal insufficiency or failure;
• Hepatitis; jaundice; acute hepatic necrosis or failure;
• Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
Discontinue CIPRO IV immediately at the first appearance of a skin rash, jaundice, or any other sign of
hypersensitivity and supportive measures instituted [see Adverse Reactions (6.1, 6.2)].
5.5 Hepatotoxicity
Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal
events, have been reported with CIPRO IV. Acute liver injury is rapid in onset (range 1–39 days), and is
often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed.
Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms
of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment
immediately.
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice,
especially in patients with previous liver damage, who are treated with CIPRO IV. [See Adverse
Reactions (6.2, 6.3).]
5.6 Serious Adverse Reactions with Concomitant Theophylline
Serious and fatal reactions have been reported in patients receiving concurrent administration of
Intravenous CIPRO and theophylline. These reactions have included cardiac arrest, seizure, status
epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have
also occurred.
Although similar serious adverse reactions have been reported in patients receiving theophylline alone,
the possibility that these reactions may be potentiated by CIPRO cannot be eliminated. If concomitant use
cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Drug
Interactions (7).]
5.7 Central Nervous System Effects
Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have
been reported in patients receiving fluoroquinolones, including CIPRO IV. CIPRO IV may also cause
central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares,
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paranoia, dizziness, confusion, tremors, hallucinations, depression, and, psychotic reactions have
progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed
suicide. These reactions may occur following the first dose. Advise patients receiving CIPRO IV to
inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute
appropriate care. CIPRO IV, like other fluoroquinolones, is known to trigger seizures or lower the seizure
threshold. As with all fluoroquinolones, use CIPRO with caution in epileptic patients and patients with
known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for
example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow,
altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures
or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). Use CIPRO IV
when the benefits of treatment exceed the risks, since these patients are endangered because of possible
undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur,
discontinue CIPRO. [See Adverse Reactions (6.1) and Drug Interactions (7).]
5.8 Clostridium Difficile-Associated Diarrhea
Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including CIPRO IV, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.
difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients
who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD
has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial
treatment of C. difficile, and institute surgical evaluation as clinically indicated. [See Adverse Reactions
(6.1).]
5.9 Peripheral Neuropathy
Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in
paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving
fluoroquinolones, including CIPRO IV. Symptoms may occur soon after initiation of CIPRO IV and may
be irreversible. Discontinue CIPRO IV immediately if the patient experiences symptoms of peripheral
neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in
sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor
strength in order to minimize the development of an irreversible condition. [See Adverse Reactions (6.1,
6.2).]
5.10 Prolongation of the QT Interval
Some fluoroquinolones, including CIPRO IV, have been associated with prolongation of the QT interval
on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during
postmarketing surveillance in patients receiving fluoroquinolones, including CIPRO IV. Avoid CIPRO IV
in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de
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pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as
hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or
bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class
III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.
Elderly patients may also be more susceptible to drug-associated effects on the QT interval. [See Adverse
Reactions (6.2) and Use in Specific Populations (8.5).]
5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
CIPRO IV is indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of
inhalational anthrax (post exposure), and plague [see Indications and Usage (1.10, 1.11, 1.12)]. An
increased incidence of adverse reactions compared to controls, including reactions related to joints and/or
surrounding tissues, has been observed [see Adverse Reactions (6.1)].
In pre-clinical studies, oral administration of CIPRO IV caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. [See Use in Specific Populations
(8.4) and Nonclinical Toxicology (13.2).]
5.12 Crystalluria
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in
the urine of laboratory animals, which is usually alkaline [see Nonclinical Toxicology (13.2)]. Crystalluria
related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic.
Avoid alkalinity of the urine in patients receiving CIPRO IV. Hydrate patients well to prevent the
formation of highly concentrated urine [see Dosage and Administration (2.4)].
5.13 Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as
exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema)
involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the
forearms, dorsa of the hands), can be associated with the use of quinolones, including CIPRO IV, after
sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue
CIPRO IV if phototoxicity occurs. [See Adverse Reactions (6.1).]
5.14 Development of Drug Resistant Bacteria
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
5.15 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2
Enzymes
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of CIPRO IV
and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine,
tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co
administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co
administered drug. [See Drug Interactions (7) and Clinical Pharmacology (12.3).]
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5.16 Periodic Assessment of Organ System Functions
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
6 ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail
in other sections of labeling:
• Tendon Effects [see Warnings and Precautions (5.1)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.4)]
• Hepatotoxicity [see Warnings and Precautions (5.5)]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions
(5.6)]
• Central Nervous System Effects [see Warnings and Precautions (5.7)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.8)]
• Peripheral Neuropathy [see Warnings and Precautions (5.9)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.10)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.11)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adult Patients
During clinical investigations with oral and parenteral CIPRO IV, 49,038 patients received courses of the
drug.
The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
In clinical trials the following adverse reactions were reported in greater than 1% of patients treated with
intravenous CIPRO IV: nausea, diarrhea, central nervous system disturbance, local intravenous site
reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Local intravenous
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin
reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is
not contraindicated unless the reactions recur or worsen.
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Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin
Patients
System Organ Class
Adverse Reactions
Body as a Whole
Abdominal Pain/Discomfort
Pain
Cardiovascular
Cardiopulmonary Arrest
Myocardial Infarction
Tachycardia
Syncope
Hypertension
Angina Pectoris
Vasodilation
Central Nervous System
Restlessness
Seizures (including Status Epilepticus)
Paranoia
Psychosis (toxic)
Depression (potentially culminating in self-injurious behavior,
such as suicidal ideations/thoughts and attempted or completed
suicide)
Phobia
Depersonalization
Manic Reaction
Unresponsiveness
Ataxia
Hallucinations
Dizziness
Paresthesia
Tremor
Insomnia
Nightmares
Irritability
Malaise
Abnormal Gait
Migraine
Gastrointestinal
Ileus
Gastrointestinal Bleeding
Pancreatitis
Hepatic Necrosis
Intestinal Perforation
Dyspepsia
Constipation
Oral Ulceration
Mouth Dryness
Anorexia
Flatulence
Hepatitis
Hemic/Lymphatic
Agranulocytosis
Prolongation of Prothrombin Time
Petechia
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System Organ Class
Adverse Reactions
Metabolic/Nutritional
Hyperglycemia
Hypoglycemia
Musculoskeletal
Arthralgia
Joint Stiffness
Muscle Weakness
Renal/Urogenital
Renal Failure
Interstitial Nephritis
Hemorrhagic Cystitis
Renal Calculi
Frequent Urination
Gynecomastia
Crystalluria
Cylindruria
Hematuria
Albuminuria
Respiratory
Respiratory Arrest
Dyspnea
Laryngeal Edema
Hemoptysis
Bronchospasm
Skin/Hypersensitivity
Allergic Reactions
Anaphylactic Reactions including life-threatening anaphylactic
shock
Erythema Multiforme/Stevens-Johnson Syndrome
Exfoliative Dermatitis
Toxic Epidermal Necrolysis
Vasculitis
Angioedema
extremities
Purpura
Fever
Pruritus
Urticaria
Increased Perspiration
Erythema Nodosum
Thrombophlebitis
Burning
Photosensitivity/Phototoxicity Reaction
Special Senses
Decreased Visual Acuity
Blurred Vision
Disturbed Vision (diplopia, chromatopsia, and photopsia)
Anosmia
Hearing Loss
Tinnitus
Nystagmus
Bad Taste
14
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In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing CIPRO (Intravenous and
Intravenous/Oral. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction
profile of CIPRO was comparable to that of the control drugs.
Pediatric Patients
Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous
ciprofloxacin was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration
of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A
total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6
weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal
adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually
within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution
of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse
reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse
reactions was consistently higher in the ciprofloxacin group compared to the control group across all age
subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period
was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated
patients (Table 6).
Table 6: Musculoskeletal Adverse Reactions1 as Assessed by the IPSC
CIPRO
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval2
(-0.8%, +7.2%)
Age Group
12 months to 24 months
1/36 (2.8%)
0/41
2 years to <6 years
5/124 (4%)
3/118 (2.5%)
6 years to <12 years
18/143 (12.6%)
12/153 (7.8%)
12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval2
(-0.6%, + 9.1%)
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1.
Included: arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain,
myalgia, arm pain, and decreased range of motion in a joint (knee, elbow, ankle, hip, wrist, and shoulder)
2.
The study was designed to demonstrate that the arthropathy rate for the CIPRO group did not exceed that of the control
group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could
not be concluded that the ciprofloxacin group had findings comparable to the control group.
The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness,
nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were
41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most
frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9%
(31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse
reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%,
vomiting 4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for
the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5–17 years). Sixty seven
patients received CIPRO IV 10 mg/kg/dose every 8 hours for one week followed by CIPRO tablets 20
mg/kg/dose every 12 hours to complete 10–21 days treatment and 62 patients received the combination of
ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8
hours for a total of 10–21 days. Periodic musculoskeletal assessments were conducted by treatment-
blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0–
93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin
group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects
in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the
patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were
similar in nature and frequency between treatment arms. The efficacy of CIPRO for the treatment of acute
pulmonary exacerbations in pediatric cystic fibrosis patients has not been established.
In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected
that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur
in pediatric patients.
6.2 Postmarketing Experience
The following adverse reactions have been reported from worldwide marketing experience with
fluoroquinolones, including CIPRO IV. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure (Table 7).
Table 7: Postmarketing Reports of Adverse Drug Reactions
System Organ Class
Adverse Reactions
Cardiovascular
QT prolongation
Torsade de Pointes
Vasculitis and ventricular arrhythmia
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Central Nervous System
Hypertonia
Myasthenia
Exacerbation of myasthenia gravis
Peripheral neuropathy
Polyneuropathy
Twitching
Eye Disorders
Nystagmus
Gastrointestinal
Pseudomembranous colitis
Hemic/Lymphatic
Pancytopenia (life threatening or fatal outcome)
Methemoglobinemia
Hepatobiliary
Hepatic failure (including fatal cases)
Infections and Infestations
Candidiasis (oral, gastrointestinal, vaginal)
Investigations
Prothrombin time prolongation or decrease
Cholesterol elevation (serum)
Potassium elevation (serum)
Musculoskeletal
Myalgia
Myoclonus
Tendinitis
Tendon rupture
Psychiatric Disorders
Agitation
Confusion
Delirium
Skin/Hypersensitivity
Acute generalize exanthematous pustulosis
(AGEP)
Fixed eruption
Serum sickness-like reaction
Special Senses
Anosmia
Hyperesthesia
Hypesthesia
Taste loss
6.3 Adverse Laboratory Changes
Changes in laboratory parameters while on CIPRO IV therapy are listed below:
• Hepatic-Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin
• Hematologic-Elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
• Renal-Elevations of serum creatinine, BUN, and uric acid
• Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring were: decreased leukocyte count, elevated atypical lymphocyte count, immature
WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT), decreased
BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum
potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring during
administration of ciprofloxacin were: elevation of serum amylase, decrease of blood glucose,
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pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased
prothrombin time, hemolytic anemia, and bleeding diathesis.
7 DRUG INTERACTIONS
Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co
administration of CIPRO IV with other drugs primarily metabolized by CYP1A2 results in increased
plasma concentrations of these drugs and could lead to clinically significant adverse events of the co
administered drug.
Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and CIPRO IV
is contraindicated due to the potentiation of hypotensive
and sedative effects of tizanidine [see Contraindications
(4.2)]
Theophylline
Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of CIPRO IV with
theophylline may result in increased risk of a patient
developing central nervous system (CNS) or other
adverse reactions. If concomitant use cannot be avoided,
monitor serum levels of theophylline and adjust dosage
as appropriate. [See Warnings and Precautions (5.6).]
Drugs Known to
Prolong QT Interval
Avoid Use
CIPRO IV may further prolong the QT interval in
patients receiving drugs known to prolong the QT
interval (for example, class IA or III antiarrhythmics,
tricyclic antidepressants, macrolides, antipsychotics)
[see Warnings and Precautions (5.10) and Use in
Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution
Glucose-lowering effect
potentiated
Hypoglycemia sometimes severe has been reported
when CIPRO IV and oral antidiabetic agents, mainly
sulfonylureas (for example, glyburide, glimepiride),
were co-administered, presumably by intensifying the
action of the oral antidiabetic agent. Fatalities have been
reported. Monitor blood glucose when ciprofloxacin is
co-administered with oral antidiabetic drugs. [See
Adverse Reactions (6.1).]
Phenytoin
Use with caution
Altered serum levels of
phenytoin (increased and
decreased)
To avoid the loss of seizure control associated with
decreased phenytoin levels and to prevent phenytoin
overdose-related adverse reactions upon CIPRO IV
discontinuation in patients receiving both agents,
monitor phenytoin therapy, including phenytoin serum
concentration during and shortly after co-administration
of CIPRO IV with phenytoin.
Cyclosporine
Use with caution
(transient elevations in serum
creatinine)
Monitor renal function (in particular serum creatinine)
when ciprofloxacin is co-administered with
cyclosporine.
Anti-coagulant drugs
Use with caution
The risk may vary with the underlying infection, age and
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Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
(Increase in anticoagulant effect)
general status of the patient so that the contribution of
CIPRO IV to the increase in INR (international
normalized ratio) is difficult to assess. Monitor
prothrombin time and INR frequently during and shortly
after co-administration of CIPRO IV with an oral anti
coagulant (for example, warfarin).
Methotrexate
Use with caution
Inhibition of methotrexate renal
tubular transport potentially
leading to increased
methotrexate plasma levels
Potential increase in the risk of methotrexate associated
toxic reactions. Therefore, carefully monitor patients
under methotrexate therapy when concomitant CIPRO
IV therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and
appropriate dose adjustment of ropinirole is
recommended during and shortly after co-administration
with CIPRO IV [see Warnings and Precautions (5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse
reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with
CIPRO IV are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl
salicylic acid) in combination of very high doses of
quinolones have been shown to provoke convulsions in
pre-clinical studies and in postmarketing.
Sildenafil
Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity (see Pharmacokinetics
12.3).
Duloxetine
Avoid Use
Five-fold increase in duloxetine
exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in
elevated levels and prolongation
of serum half-life
CIPRO IV inhibits the formation of paraxanthine after
caffeine administration (or pentoxifylline containing
products). Monitor for xanthine toxicity and adjust dose
as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid
Use with caution
(interferes with renal tubular
secretion of CIPRO and
increases CIPRO serum levels)
Potentiation of CIPRO IV toxicity may occur.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. CIPRO IV should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An
expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the
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Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a
substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that
there is no risk.2
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3 In utero exposure to
fluoroquinolones during embryogenesis was not associated with increased risk of major malformations.
The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6%
for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).4 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were
both within background incidence ranges. No specific patterns of congenital abnormalities were found.
The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.2, 3 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses.
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3
times the maximum daily human dose based upon body surface area, respectively) and have revealed no
evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100
mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body
surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed.
8.3 Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is
unknown. Because of the potential risk of serious adverse reactions (including articular damage) in
infants nursing from mothers taking CIPRO IV, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Although effective in clinical trials, CIPRO IV is not a drug of first choice in the pediatric population due
to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO IV,
cause arthropathy in juvenile animals [see Warnings and Precautions (5.11) and Nonclinical Toxicology
(13.2)].
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Complicated Urinary Tract Infection and Pyelonephritis
CIPRO IV is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric
patients 1 to 17 years of age. Although effective in clinical trials, CIPRO IV is not a drug of first choice in
the pediatric population due to an increased incidence of adverse reactions compared to the controls,
including events related to joints and/or surrounding tissues. [See Adverse Reactions (6.1) and Clinical
Studies (14.2).]
Inhalational Anthrax (Post-Exposure)
CIPRO IV is indicated in pediatric patients from birth to 17 years of age for inhalational anthrax (post
exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients
is appropriate [see Dosage and Administration (2.2) and Clinical Studies (14.3)].
Plague
CIPRO IV is indicated in pediatric patients from birth to 17 years of age, for treatment of plague,
including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague.
Efficacy studies of CIPRO IV could not be conducted in humans with pneumonic plague for feasibility
reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The
risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate. [See
Indications and Usage (1.12), Dosage and Administration (2.2), and Clinical Studies (14.4).]
8.5 Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture
when being treated with a fluoroquinolone such as CIPRO IV. This risk is further increased in patients
receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand,
shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to
several months after fluoroquinolone treatment have been reported. Caution should be used when
prescribing CIPRO IV to elderly patients especially those on corticosteroids. Patients should be informed
of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider
if any symptoms of tendinitis or tendon rupture occur. [See Boxed Warning, Warnings and Precautions
(5.1), and Adverse Reactions (6.2).]
In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over
3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and
10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but greater sensitivity of
some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal function by virtue
of their advanced age, care should be taken in dose selection for elderly patients, and renal function
monitoring may be useful in these patients. [See Dosage and Administration (2.3) and Clinical
Pharmacology (12.3).]
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO IV with concomitant drugs that can result in
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prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). [See
Warnings and Precautions (5.10).]
8.6 Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. [See Dosage and Administration (2.3) and Clinical Pharmacology (12.3).]
8.7 Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients
with acute hepatic insufficiency, have not been studied.
10 OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Observe the
patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and
acidify, if required, to prevent crystalluria. Adequate hydration must be maintained. Only a small amount
of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125mg/kg and 300 mg/kg.
11 DESCRIPTION
CIPRO IV (ciprofloxacin) is a synthetic antimicrobial agent for intravenous (IV) administration.
Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3
quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is: structural formula
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions
are available as sterile 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. CIPRO IV
contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is not made with natural rubber latex.. Solutions in contact with the plastic container
can leach out certain of its chemical components in very small amounts within the expiration period, for
example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has
been confirmed in tests in animals according to USP biological tests for plastic containers as well as by
tissue culture toxicity studies.
The glucose content for the 200 mL flexible container is 10 g.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].
12.3 Pharmacokinetics
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg CIPRO IV to normal volunteers, the
mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively (Table 9).
Table 9: Steady-state Ciprofloxacin Serum Concentrations (mcg/mL)
After 60-minute INTRAVENOUS Infusions every 12 hours.
Time after starting the infusion
Dose
30 minutes
1 hour
3 hour
6 hour
8 hour
12 hour
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose
on an every 12 hour regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by
first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12
hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to
that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state
equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg intravenous dose
results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given
every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours
(Table 10).
Table 10: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous
Doses
Parameters
500 mg
400 mg
750 mg
400 mg
every 12 hours
every 12 hours,
every 12 hours,
every 8
AUC (mcg•hr/mL)
Orally.
13.71
intravenously
12.71
orally
31.62
hours,
32.93
Cmax (mcg/mL)
2.97
4.56
3.59
4.07
1.
AUC 0-12h
2.
AUC 24h = AUC 0-12h x 2
3.
AUC 24h = AUC 0-8h x 3
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Distribution
After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue
concentrations often exceed serum concentrations in both men and women, particularly in genital tissue
including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions,
mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into
the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism
After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The metabolites have
antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other
drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and
could lead to clinically significant adverse events of the co-administered drug [see Contraindications
(4.2), Warnings and Precautions (5.6, 5.15) Drug Interactions (7)].
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg intravenous dose, concentrations in the urine usually exceed 200
mcg/mL 0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing.
Following a 400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after
dosing and are usually greater than 30 mcg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (<less than1%) is recovered from the
bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5
days after dosing.
Specific Populations
Elderly
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older
than 65 years) as compared to young adults. Although the Cmax is increased 16% to40%, the increase in
mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in
the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. [See Use in Specific Populations (8.5).]
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required [see Use in Specific Populations (8.6), Dosage and Administration (2.3)].
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Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute
hepatic insufficiency, have not been fully studied.
Pediatrics
Following a single oral dose of 10 mg/kg CIPRO suspension to 16 children ranging in age from 4 months
to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2
mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*hr/mL). There was no apparent age-dependence, and no
notable increase in Cmax or AUC upon multiple dosing (10 mg/kg three times a day). In children with
severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax
was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2
mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The
AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32.0 mcg*hr/mL) and 16.5 mcg*hr/mL
(range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective age groups. These values are within the
range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 hours–5 hours,
and the bioavailability of the oral suspension is approximately 60%.
Drug-Drug Interactions
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly
increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500
mg twice a day for 3 days). Concomitant administration of tizanidine and CIPRO IV is
contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see
Contraindications (4.2)].
Ropinirole
In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once
daily with 500 mg CIPRO twice-daily, the mean Cmax and mean AUC of ropinirole were increased by
60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose
adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see
Warnings and Precautions (5.15)].
Clozapine
Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum
concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively.
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with CIPRO IV are advised.
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Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to
healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold.
Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in
the exposure of sildenafil upon co-administration of CIPRO IV.
Duloxetine
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the
CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold
increase in mean Cmax of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg
ciprofloxacin twice daily resulted in an increase of lidocaine Cmax and AUC by 12% and 26%,
respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible
interaction with CIPRO IV and an increase in adverse reactions related to lidocaine may occur upon
concomitant administration.
12.4 Microbiology
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA
replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones
occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or
drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to
ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6
.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro
and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Bacillus anthracis
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
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Gram-negative bacteria
Citrobacter koseri
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Yersinia pestis
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of
the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to
the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in
treating clinical infections due to these bacteria has not been established in adequate and well-controlled
clinical trials.
Gram-positive bacteria
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
Gram-negative bacteria
Acinetobacter lwoffi
Aeromonas hydrophila
Edwardsiella tarda
Enterobacter aerogenes
Klebsiella oxytoca
Legionella pneumophila
Pasteurella multocida
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Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility
test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports
that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports
should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.
The MICs should be determined using a standardized test method (broth and/or agar).5, 6, 7 The MIC
values should be interpreted according to criteria provided in Table 10.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the
susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a
standardized test method.6, 7, 8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to
test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in
Table 11.
Table 11: Susceptibility Test Interpretive Criteria for Ciprofloxacin
MIC (mcg/mL)
Zone Diameter (mm)
Bacteria
S
I
R
S
I
R
Enterobacteriaceae
≤1
2
≥4
≥21
16–20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus aureus
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus epidermidis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus saprophyticus
≤1
2
≥4
≥21
16–20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16–20
≤15
Haemophilus influenzae1
≤1
-
-
≥21
-
-
Haemophilus parainfluenzae1
≤1
-
-
≥21
-
-
Streptococcus pneumoniae
≤1
2
≥4
≥21
16–20
≤15
Streptococcus pyogenes
≤1
2
≥4
≥21
16–20
≤15
Bacillus anthracis1
≤0.25
-
-
-
-
-
Yersinia pestis1
≤0.25
-
-
-
-
-
S=Susceptible, I=Intermediate, and R=Resistant.
1.
The current absence of data on resistant isolates precludes defining any results other than “Susceptible”. If isolates yield
MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the
antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of
the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if
the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be
repeated. This category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be used. This category also
provides a buffer zone that prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to
inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
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Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy
and precision of supplies and reagents used in the assay, and the techniques of the individuals performing
the test.5, 6, 7, 8 Standard ciprofloxacin powder should provide the following range of MIC values noted in
Table 12. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 12 should be
achieved.
Table 12: Acceptable Quality Control Ranges for Ciprofloxacin
Bacteria
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03
34–42
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC 29213
0.12–0.5
-
Staphylococcus aureus ATCC 25923
-
22–30
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A total of 8 in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are
listed below:
• Salmonella/Microsome Test (Negative)
• E. coli DNA Repair Assay (Negative)
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V79 Cell HGPRT Test (Negative)
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerevisiae Point Mutation Assay (Negative)
• Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte DNA Repair Assay (Positive)
• Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due
to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively
(approximately 1.7- times and 2.5- times the highest recommended therapeutic dose based upon body
surface area, respectively).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
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recommended human dose based upon body surface area), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to32 weeks
in mice treated concomitantly with UVA and other quinolones.9
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no
data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times
the highest recommended therapeutic dose based upon body surface area) revealed no evidence of
impairment.
13.2 Animal Toxicology and/or Pharmacology
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested [see Warnings and Precautions (5.11)].
Damage of weight-bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30
mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral
ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- times and 3.5-times the
pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes
which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg
(approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints
were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free
period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did
not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon body
surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release, since they
are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection
also produces hypotension but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and
indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals
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14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of CIPRO IV, 400 mg intravenously every 8 hours, in combination with
piperacillin sodium, 50 mg/kg intravenously every 4 hours, for the empirical therapy of febrile
neutropenic patients were studied in one large pivotal multicenter, randomized trial and were compared to
those of tobramycin, 2 mg/kg intravenously every 8 hours, in combination with piperacillin sodium, 50
mg/kg intravenously every 4 hours.
Clinical response rates observed in this study were as follows:
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 13.
Table 13: Clinical Response Rates
Outcomes
CIPRO IV/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of Initial
63 (27%)
52 (21.9%)
Febrile Episode with No
Modifications of Empirical
Regimen1
Clinical Resolution of Initial
187 (80.3%)
185 (78.1%)
Febrile Episode Including
Patients with Modifications of
Empirical Regimen
Overall Survival
224 (96.1%)
185 (78.1%)
1.
To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological eradication of
infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of infection; and (4) no
modification of empirical antibiotic regimen
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in Pediatric
Patients
Ciprofloxacin, administered IV and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 14.
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Table 14: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment1
84.4% (178/211)
78.3% (181/231)
95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
1.
Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were
5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.
14.3 Inhalational Anthrax in Adults and Pediatrics
Additional information
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in
survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been
evaluated in various human populations. The mean peak serum concentration achieved at steady-state in
human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400
mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these
regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak
plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26
mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After
the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin
serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication.11
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5
x 105) spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration
(MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied,
mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral
dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL.10 Mortality due to
anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-
exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.11
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More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were
also given anthrax vaccine or were switched to alternative antibacterial drugs. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
14.4 Plague
A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110
LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean
peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49
mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day
6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day
6 and Day 10) were < 0.5 mcg/mL. Animals were randomized to receive either a 10-day regimen of
intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body
temperature greater than 1.5oC over baseline for two hours), or at 76 hours post-challenge, whichever
occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the
placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one
ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure
of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all
timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of
low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was
negative.12
15 REFERENCES
1. 21 CFR 314.510 (Subpart H–Accelerated Approval of New Drugs for Life-Threatening Illnesses).
2. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6):1336-1339.
4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS).
Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
5. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–9th Edition. CLSI
Document M7-A9 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite
2500, Wayne, PA, 19087-1898.
Reference ID: 3695262
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing; 24th Informational Supplement. CLSI Document M100 S24 [2014]. Clinical
and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–2nd
Edition. CLSI Document M45-A2 [2010]. Clinical and Laboratory Standards Institute, 950 West
Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
8. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk
Susceptibility Tests; Approved Standard–11th Edition. CLSI Document M2-A11[2012]. Clinical and
Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
9. CReport presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory
Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER,
Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852,
USA.
10. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
11. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167:1239-42.
12. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for
treatment of Pneumonic Plague.
16 HOW SUPPLIED/STORAGE AND HANDLING
CIPRO IV (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution in flexible
containers not made with natural rubber latex.
SIZE
STRENGTH
NDC NUMBER
200 mL
5% Dextrose 400 mg, 0.2%
50419-759-01
STORAGE
Store between 5–25ºC (41–77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-Approved patient labeling (Medication Guide)
Antibacterial Resistance
Inform patients that antibacterial drugs including CIPRO IV should only be used to treat bacterial
infections. They do not treat viral infections (for example, the common cold). When CIPRO IV prescribed
to treat a bacterial infection, patients should be told that although it is common to feel better early in the
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course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing
the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable by CIPRO IV or other
antibacterial drugs in the future.
Administration
Inform patients to drink fluids liberally while taking CIPRO to avoid formation of highly concentrated
urine and crystal formation in the urine.
Serious and Potentially Serious Adverse Reactions
Inform patients of the following serious adverse reactions that have been associated with CIPRO or other
fluoroquinolone use:
• Tendon Disorders Instruct patients to contact their healthcare provider if they experience pain,
swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and
refrain from exercise; and discontinue CIPRO treatment. The risk of severe tendon disorder with
fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of
myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of
muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions,
even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other
skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting
angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or
other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events)
has been reported in patients taking CIPRO IV. Instruct patients to inform their physician if they
experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever,
weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light
colored bowel movements or dark colored urine.
• Convulsions: Inform patients that convulsions have been reported in patients receiving
fluoroquinolones, including ciprofloxacin. Instruct patients to notify their physician before taking this
drug if they have a history of convulsions.
• Neurologic Adverse Effects (for example, dizziness, lightheadedness, increased intracranial
pressure): Inform patients that they should know how they react to CIPRO IV before they operate an
automobile or machinery or engage in other activities requiring mental alertness and coordination.
Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop
watery and bloody stools (with or without stomach cramps and fever) even as late as two or more
months after having taken the last dose of the antibiotic. If this occurs, Instruct patients to contact
their physician as soon as possible.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with
ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible If
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symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, immediately discontinue CIPRO IV and contact their physician.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or
family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or
recent myocardial ischemia if they are taking any Class IA (quinidine, procainamide), or Class III
(amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have
any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of
consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician
if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric
patients to notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.4)].
• Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine.
Ciprofloxacin increases the effects of tizanidine (Zanaflex®).
• Theophylline: Inform patients that ciprofloxacin CIPRO IV may increase the effects of theophylline.
Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek
medical help if they experience seizures, palpitations, or difficulty breathing.
• Caffeine: Inform patients that ciprofloxacin may increase the effects of caffeine. There is a
possibility of caffeine accumulation when products containing caffeine are consumed while taking
quinolones.
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported
in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or
artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be
outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun
exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or
skin eruption occurs, instruct patients to contact their physician.
Drug Interactions Oral Antidiabetic Agents
Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were
co-administered; if low blood sugar occurs with CIPRO IV, instruct them toconsult their physician and
that their antibacterial medicine may need to be changed.
Anthrax and Plague Studies
Inform patients given CIPRO IV for this condition that efficacy studies could not be conducted in humans
for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies
conducted in animals.
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Medication Guide
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
for oral suspension
CIPRO® XR (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® IV (Sip-row)
(ciprofloxacin)
Injection
for intravenous infusion
Read this Medication Guide before you start taking CIPRO and each time you get a
refill. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO, a fluoroquinolone antibacterial medicine, can cause serious side
effects. Some of these serious side effects could result in death.
If you get any of the following serious side effects while you take CIPRO, get
medical help right away. Talk with your healthcare provider about whether you
should continue to take CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis).
•
Tendon problems can happen in people of all ages who take CIPRO.
Tendons are tough cords of tissue that connect muscles to bones.
Symptoms of tendon problems may include:
o pain
o swelling
o tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
• The risk of getting tendon problems while you take CIPRO is higher if
you:
o are over 60 years of age
o are taking steroids (corticosteroids)
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o have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO.
• Other reasons that can increase your risk of tendon problems can include:
o physical activity or exercise
o kidney failure
o tendon problems in the past, such as in people with rheumatoid arthritis
(RA)
• Call your healthcare provider right away at the first sign of tendon
pain, swelling or inflammation. Stop taking CIPRO until tendinitis or
tendon rupture has been ruled out by your healthcare provider. Avoid
exercise and using the affected area.
The most common area of pain and swelling is the Achilles tendon at the
back of your ankle. This can also happen with other tendons. Talk to your
healthcare provider about the risk of tendon rupture with continued use of
CIPRO. You may need a different antibiotic that is not a fluoroquinolone to
treat your infection.
• Tendon rupture can happen while you are taking or after you have
finished taking CIPRO. Tendon ruptures have happened up to several
months after people have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or
symptoms of a tendon rupture:
o hear or feel a snap or pop in a tendon area
o bruising right after an injury in a tendon area
o unable to move the affected area or bear weight
2. Worsening of myasthenia gravis (a problem that causes muscle
weakness). Fluoroquinolones like CIPRO may cause worsening of myasthenia
gravis symptoms, including muscle weakness and breathing problems. Call your
healthcare provider right away if you have any worsening muscle weakness or
breathing problems.
See “What are the possible side effects of CIPRO?”
What is CIPRO?
CIPRO is a fluoroquinolone antibacterial medicine used in adults age 18 years and
older to treat certain infections caused by certain germs called bacteria. These
bacterial infections include:
• urinary tract infection
• chronic prostate infection
• lower respiratory tract infection
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• sinus infection
• skin infection
• bone and joint infection
• nosocomial pneumonia
• intra-abdominal infection, complicated
• infectious diarrhea
• typhoid (enteric) fever
• cervical and urethral gonorrhea, uncomplicated
• people with a low white blood cell count and a fever
• inhalational anthrax
• plague
• Studies of CIPRO for use in the treatment of plague and anthrax were done in
animals only, because plague and anthrax could not be studied in people.
• CIPRO is also used in children younger than 18 years of age to treat
complicated urinary tract and kidney infections or who may have breathed in
anthrax germs, have plague or have been exposed to plague germs.
• Children younger than 18 years of age have a higher chance of getting bone,
joint, or tendon (musculoskeletal) problems such as pain or swelling while taking
CIPRO. CIPRO should not be used as the first choice of antibacterial medicine in
children under 18 years of age.
• CIPRO XR is only used in adults 18 years of age and older to treat urinary
tract infections (complicated and uncomplicated), including kidney infections
(pyelonephritis).
• It is not known if CIPRO XR is safe and effective in children under 18 years of
age.
Who should not take CIPRO?
Do not take CIPRO if you:
• Have ever had a severe allergic reaction to an antibacterial medicine known as a
fluoroquinolone, or are allergic to ciprofloxacin hydrochloride or any of the
ingredients in CIPRO. See the end of this Medication Guide for a complete list of
ingredients in CIPRO.
•
Also take a medicine called tizanidine (Zanaflex®).
Ask your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking CIPRO?
Before you take CIPRO, tell your healthcare provider if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis)
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• have liver problems
• have central nervous system problems (such as epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition
called “QT prolongation”
• have or have had seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do
not work well.
• have joint problems including rheumatoid arthritis (RA)
• have trouble swallowing pills
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if CIPRO will harm
your unborn baby.
• are breastfeeding or plan to breastfeed. CIPRO passes into breast milk. You and
your healthcare provider should decide whether you will take CIPRO or
breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
CIPRO and other medicines can affect each other causing side effects.
Especially tell your healthcare provider if you take:
• a steroid medicine
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• theophylline (such as Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• a medicine to control your heart rate or rhythm (antiarrhythmics)
• an oral anti-diabetes medicine
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin® ,
Extended Phenytoin Sodium®, Prompt Phenytoin Sodium®, Phenytek®)
• cyclosporine (Gengraf®, Neoral®, Sandimmune®, Sangcya®).
• a blood thinner (such as warfarin, Coumadin®, Jantoven®)
• methotrexate (Trexall®)
• ropinirole (Requip®)
• clozapine (Clozaril®, Fazaclo® ODT®)
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• a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many common medicines for
pain relief are NSAIDs. Taking an NSAID while you take CIPRO or other
fluoroquinolones may increase your risk of central nervous system effects and
seizures.
• sildenafil (Viagra®, Revatio®)
• duloxetine
• products that contain caffeine
• probenecid (Probalan®, Col-probenecid ®)
• certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from
working correctly. Take CIPRO Tablets and Oral Suspension either 2 hours
before or 6 hours after taking these medicines, vitamins, or supplements:
o an antacid, multivitamin, or other medicine or supplements that has
magnesium, calcium, aluminum, iron, or zinc
o sucralfate (Carafate®)
o didanosine (Videx®, Videx EC®)
Ask your healthcare provider for a list of these medicines if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much CIPRO to take and when to take
it.
• Take CIPRO Tablets in the morning and evening at about the same time each
day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your
healthcare provider if you cannot swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time
each day. Shake the CIPRO Oral Suspension bottle well each time before use for
about 15 seconds to make sure the suspension is mixed well. Close the bottle
completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare
provider if you cannot swallow the tablet whole.
• CIPRO IV is given to you by intravenous (IV) infusion into your vein, slowly,
over 60 minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-
fortified juices alone, but may be taken with a meal that contains these
products.
Reference ID: 3695262
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses of CIPRO, or stop taking it, even if you begin to feel
better, until you finish your prescribed treatment unless:
o you have tendon problems. See “What is the most important
information I should know about CIPRO?”
o you have a serious allergic reaction. See “What are the possible side
effects of CIPRO?”
o your healthcare provider tells you to stop taking CIPRO
Taking all of your CIPRO doses will help make sure that all of the bacteria are
killed. Taking all of your CIPRO doses will help lower the chance that the
bacteria will become resistant to CIPRO. If you become resistant to CIPRO,
CIPRO and other antibacterial medicines may not work for you in the future.
• If you take too much CIPRO, call your healthcare provider or get medical help
right away.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate
machinery, or do other activities that require mental alertness or coordination
until you know how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can
make your skin sensitive to the sun (photosensitivity) and the light from
sunlamps and tanning beds. You could get a severe sunburn, blisters or swelling
of your skin. If you get any of these symptoms while you take CIPRO, call your
healthcare provider right away. You should use a sunscreen and wear a hat and
clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
CIPRO may cause serious side effects, including:
• See, “What is the most important information I should know about
CIPRO?”
• Serious allergic reactions. Serious allergic reactions, including death, can
happen in people taking fluoroquinolones, including CIPRO, even after only 1
dose. Stop taking CIPRO and get emergency medical help right away if you get
any of the following symptoms of a severe allergic reaction:
o hives
o trouble breathing or swallowing
o swelling of the lips, tongue, face
o throat tightness, hoarseness
o rapid heartbeat
o faint
Reference ID: 3695262
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o skin rash
Skin rash may happen in people taking CIPRO even after only 1 dose. Stop
taking CIPRO at the first sign of a skin rash and call your healthcare provider.
Skin rash may be a sign of a more serious reaction to CIPRO.
• Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who
take CIPRO. Call your healthcare provider right away if you have unexplained
symptoms such as:
o nausea or vomiting
o unusual tiredness
o stomach pain
o loss of appetite
o fever
o light colored bowel
movements
o weakness
o dark colored urine
o abdominal pain or
tenderness
o yellowing of your skin or the
whites of your eyes
o itching
Stop taking CIPRO and tell your healthcare provider right away if you have
yellowing of your skin or white part of your eyes, or if you have dark urine.
These can be signs of a serious reaction to CIPRO (a liver problem).
• Central Nervous System (CNS) effects. Seizures have been reported in
people who take fluoroquinolone antibacterial medicines, including CIPRO. Tell
your healthcare provider if you have a history of seizures. Ask your healthcare
provider whether taking CIPRO will change your risk of having a seizure.
CNS side effects may happen as soon as after taking the first dose of CIPRO.
Talk to your healthcare provider right away if you get any of these side effects,
or other changes in mood or behavior:
o seizures
o trouble sleeping
o hear voices, see things, or
o nightmares
sense things that are not there
o feel lightheaded or dizzy
(hallucinations)
o feel more suspicious (paranoia)
o feel restless
o suicidal thoughts or acts
o tremors
o headaches that will not go away,
o feel anxious or nervous
with or without blurred vision
o confusion
o depression
• Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen
with many antibacterial medicines, including CIPRO. Call your healthcare provider right away
if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have
stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after
you have finished your antibacterial medicine.
43
Reference ID: 3695262
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage
to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones,
including CIPRO. Talk with your healthcare provider right away if you get any of the following
symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
o pain
o burning
o tingling
o numbness
o weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Serious heart rhythm changes (QT prolongation and torsade de pointes). Tell your
healthcare provider right away if you have a change in your heart beat (a fast or irregular
heartbeat), or if you faint. CIPRO may cause a rare heart problem known as prolongation of
the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous.
The chances of this event are higher in people:
o who are elderly
o with a family history of prolonged QT interval
o with low blood potassium (hypokalemia)
o who take certain medicines to control heart rhythm (antiarrhythmics)
• Joint Problems. Increased chance of problems with joints and tissues around joints in
children under 18 years old can happen. Tell your child’s healthcare provider if your child has
any joint problems during or after treatment with CIPRO.
• Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking
CIPRO?”
The most common side effects of CIPRO include:
• nausea
• diarrhea
• changes in liver function tests
• vomiting
•
rash
Tell your healthcare provider about any side effect that bothers you, or that does not go away.
These are not all the possible side effects of CIPRO. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1
800-FDA-1088.
How should I store CIPRO?
CIPRO Tablets
•
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
CIPRO Oral Suspension
Reference ID: 3695262
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store microcapsules and diluent below 25°C (77°F); excursions are permitted from 15°C
to 30°C (59°F to 86°F).
• Do not freeze.
• After your CIPRO treatment is finished, safely throw away any unused oral suspension.
CIPRO XR
• Store CIPRO XR between 59°F to 86°F (15°C to 30°C).
Keep CIPRO and all medicines out of the reach of children.
General Information about the safe and effective use of CIPRO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would
like more information about CIPRO, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about CIPRO that is written for healthcare
professionals.
For more information call 1-888-842-2937.
What are the ingredients in CIPRO?
CIPRO Tablets:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene
glycol
CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients:
o Microcapsules contains: povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20
o Diluent contains: medium-chain triglycerides, sucrose, soy-lecithin, water, and
strawberry flavor
CIPRO XR:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide
CIPRO IV:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Reference ID: 3695262
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
©2015 Bayer HealthCare Pharmaceuticals Inc.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Manufactured in Italy
CIPRO (ciprofloxacin HCl) Tablets Manufactured in Germany
Revised: February 2015
Reference ID: 3695262
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:08.431524
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019847s055,019857s063lbl.pdf', 'application_number': 19847, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
11,778
|
T2002-06
89008505
Lotensin
®
benazepril hydrochloride
Tablets
Rx only
Prescribing Information
Use in Pregnancy
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause
injury and even death to the developing fetus. When pregnancy is detected, Lotensin should
be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Benazepril’s chemical name is 3-[[1-(ethoxy-carbonyl)-3-
phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid
monohydrochloride; its structural formula is
N
N
O
H
CH2COOH
H
COCH2CH3
C
O
H
CH2CH2
HCl
Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-
converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the
ester group.
Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril
hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide,
crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron
oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80,
propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and
animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the
vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by
the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Hypertensive patients treated with Lotensin alone for up to
52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with
Lotensin and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response
to angiotensin II and did not interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased
levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of
Lotensin remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin hypertension (see INDICATIONS AND
USAGE).
Pharmacokinetics and Metabolism
Following oral administration of Lotensin, peak plasma concentrations of benazepril are reached
within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery
and is not significantly influenced by the presence of food in the GI tract.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active
metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after
drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum
protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured
by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be
unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-
23.6 µmol/L).
Benazepril is almost completely metabolized to benazeprilat, which has much greater
ACE inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and
benazeprilat. Only trace amounts of an administered dose of Lotensin can be recovered in the
urine as unchanged benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as
benazepril glucuronide, and 8% as benazeprilat glucuronide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The kinetics of benazepril are approximately dose-proportional within the dosage range
of 10-80 mg.
In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of
benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat
should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.
The kinetics did not change, and there was no significant accumulation during chronic
administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios
based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects
with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-
12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance
may compensate to an extent for deficient renal clearance.
In patients with renal insufficiency, the disposition of benazepril and benazeprilat (in patients
with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min)) is similar to that
in patients with normal renal function. In patients with creatinine clearance ≤ 30 mL/min, peak
benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be
delayed (see DOSAGE AND ADMINISTRATION).
When dialysis was started two hours after ingestion of 10 mg of benazepril, approximately 6% of
benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not
detected in the dialysate.
In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are
essentially unaltered. The pharmacokinetics of benazepril and benazeprilat do not appear to be
influenced by age.
In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of
LOTENSIN (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was
0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13
L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The
terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one third
that observed in adults.
Pharmacodynamics
Single and multiple doses of 10 mg or more of Lotensin cause inhibition of plasma ACE activity
by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous
angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.
Hypertension
Adult
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administration of Lotensin to patients with mild-to-moderate hypertension results in a
reduction of both supine and standing blood pressure to about the same extent with no
compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can
occur in patients who are salt- and/or volume-depleted (see WARNINGS).
In single-dose studies, Lotensin lowered blood pressure within 1 hour, with peak
reductions achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted
for 24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6 -12 /4-7 mmHg. The trough values
represent reductions of about 50% of that seen at peak.
Four dose-response studies using once-daily dosing were conducted in 470 mild-to-
moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of
Lotensin was 10 mg; but further falls in blood pressure, especially at morning trough, were seen
with higher doses in the studied dosing range (10-80 mg). In studies comparing the same daily
dose of Lotensin given as a single morning dose or as a twice-daily dose, blood pressure
reductions at the time of morning trough blood levels were greater with the divided regimen.
During chronic therapy, the maximum reduction in blood pressure with any dose is
generally achieved after 1-2 weeks. The antihypertensive effects of Lotensin have continued
during therapy for at least two years. Abrupt withdrawal of Lotensin has not been associated
with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, Lotensin 10-20 mg was similar in
effectiveness to captopril, hydrochlorothiazide, nifedipine SR, and propranolol.
The antihypertensive effects of Lotensin were not appreciably different in patients
receiving high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a
reduction in peripheral arterial resistance, with an increase in cardiac output and renal blood flow
and little or no change in heart rate. In normal human volunteers, single doses of benazepril
caused an increase in renal blood flow but had no effect on glomerular filtration rate.
Use of Lotensin in combination with thiazide diuretics gives a blood-pressure-lowering
effect greater than that seen with either agent alone. By blocking the renin-angiotensin-
aldosterone axis, administration of Lotensin tends to reduce the potassium loss associated with
the diuretic.
Pediatric
In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic
pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or
0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85
patients whose blood pressure was reduced on therapy were then randomized to either placebo or
benazepril and were followed up for an additional two weeks. At the end of two weeks, blood
pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg
more than in children on benazepril. No dose-response was observed for the three doses.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
Lotensin is indicated for the treatment of hypertension. It may be used alone or in combination
with thiazide diuretics.
In using Lotensin, consideration should be given to the fact that another angiotensin-
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen-vascular disease. Available data are insufficient to show that
Lotensin does not have a similar risk (see WARNINGS).
Black patients receiving ACE-inhibitors have been reported to have a higher incidence of
angioedema compared to non-blacks. It should also be noted that in controlled clinical trials
ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.
CONTRAINDICATIONS
Lotensin is contraindicated in patients who are hypersensitive to this product or to any other
ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including Lotensin) may be subject to a variety of adverse reactions, some of them
serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been
reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials,
symptoms consistent with angioedema were seen in none of the subjects who received placebo
and in about 0.5% of the subjects who received Lotensin. Angioedema associated with laryngeal
edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs,
treatment with Lotensin should be discontinued and appropriate therapy instituted immediately.
Where there is involvement of the tongue, glottis, or larynx, likely to cause airway
obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL
to 0.5 mL) should be promptly administered (see ADVERSE REACTIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not
approved in the United States).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypotension
Lotensin can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has been
only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic
hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a
result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.
Volume- and/or salt-depletion should be corrected before initiating therapy with Lotensin.
In patients with congestive heart failure, with or without associated renal insufficiency,
ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria
or azotemia and, rarely, with acute renal failure and death. In such patients, Lotensin therapy
should be started under close medical supervision; they should be followed closely for the first 2
weeks of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary,
treated with intravenous infusion of physiological saline. Lotensin treatment usually can be
continued following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more
frequently in patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials
of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar
rates. Monitoring of white blood cell counts should be considered in patients with collagen-
vascular disease, especially if the disease is associated with impaired renal function.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant
women. Several dozen cases have been reported in the world literature. When pregnancy is
detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE inhibitor
exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are
exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless,
when patients become pregnant, physicians should make every effort to discontinue the use of
benazepril as soon as possible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rarely (probably less often than once in every thousand pregnancies), no alternative to
ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, benazepril should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or
biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed
for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed
toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be
required as means of reversing hypotension and/or substituting for disordered renal function.
Benazepril, which crosses the placenta, can theoretically be removed from the neonatal
circulation by these means; there are occasional reports of benefit from these maneuvers with
another ACE inhibitor, but experience is limited.
No teratogenic effects of Lotensin were seen in studies of pregnant rats, mice, and
rabbits. On a mg/m
2 basis, the doses used in these studies were 60 times (in rats), 9 times (in
mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming
a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice),
and more than 3 times (in rabbits) the maximum recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors,
including Lotensin, may be associated with oliguria and/or progressive azotemia and (rarely)
with acute renal failure and/or death. In a small study of hypertensive patients with renal artery
stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with Lotensin was
associated with increases in blood urea nitrogen and serum creatinine; these increases were
reversible upon discontinuation of Lotensin or diuretic therapy, or both. When such patients are
treated with ACE inhibitors, renal function should be monitored during the first few weeks of
This label may not be the latest approved by FDA.
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therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have
developed increases in blood urea nitrogen and serum creatinine, usually minor and transient,
especially when Lotensin has been given concomitantly with a diuretic. This is more likely to
occur in patients with preexisting renal impairment. Dosage reduction of Lotensin and/or
discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should
always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater
than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving
Lotensin. In most cases, these were isolated values which resolved despite continued therapy.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with Lotensin
(see Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Impaired Liver Function: In patients with hepatic dysfunction due to cirrhosis, levels of
benazeprilat are essentially unaltered (see WARNINGS, Hepatic Failure).
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that
produce hypotension, benazepril will block the angiotensin II formation that could otherwise
occur secondary to compensatory renin release. Hypotension that occurs as a result of this
mechanism can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors, and they should also be told that these
consequences do not appear to have resulted from intrauterine ACE inhibitor exposure that has
been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. Patients should be so advised and told to report immediately any signs or
symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in
breathing) and to take no more drug until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first days of therapy, and it should be reported to the prescribing physician.
Patients should be told that if syncope occurs, Lotensin should be discontinued until the
prescribing physician has been consulted.
All patients should be cautioned that inadequate fluid intake or excessive perspiration,
diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences
of lightheadedness and possible syncope.
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Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting the prescribing physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia.
Drug Interactions
Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently
instituted, may occasionally experience an excessive reduction of blood pressure after initiation
of therapy with Lotensin. The possibility of hypotensive effects with Lotensin can be minimized
by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment
with Lotensin. If this is not possible, the starting dose should be reduced (see DOSAGE AND
ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: Lotensin can attenuate potassium
loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride,
triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.
Therefore, if concomitant use of such agents is indicated, they should be given with caution, and
the patient’s serum potassium should be monitored frequently.
Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify
any clinically important effects on the serum concentrations or clinical effects of these
anticoagulants.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. These drugs should be
coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
Other: No clinically important pharmacokinetic interactions occurred when Lotensin was
administered concomitantly with hydrochlorothiazide, chlorthalidone, furosemide, digoxin,
propranolol, atenolol, naproxen, or cimetidine.
Lotensin has been used concomitantly with beta-adrenergic-blocking agents, calcium-
channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically
important adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive
effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by
inhibiting parts of the renin-angiotensin system.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was administered to rats and mice for
up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights,
this dose is 110 times the maximum recommended human dose. When compared on the basis of
body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum
recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic
activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in
vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. In
doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on
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mg/m
2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg
comparison), Lotensin had no adverse effect on the reproductive performance of male and
female rats.
Pregnancy Categories C (first trimester) and D (second and third
trimesters)
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk
of lactating women treated with benazepril. A newborn child ingesting entirely breast milk
would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.
Geriatric Use
Of the total number of patients who received benazepril in U.S. clinical studies of Lotensin, 18%
were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety
were observed between these patients and younger patients, and other reported clinical
experience has not identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly
patients are more likely to have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function.
Pediatric Use
The antihypertensive effects of Lotensin have been evaluated in a double- blind study in
pediatric patients 7 to 16 years of age ( see CLINICAL PHARMACOLOGY:
Pharmacodynamics and Clinical Effects, Hypertension). The pharmacokinetics of Lotensin have
been evaluated in pediatric patients 6 to 16 years of age ( see CLINICAL PHARMACOLOGY:
Pharmacokinetics and Metabolism). Lotensin was generally well tolerated and adverse effects
were similar to those described in adults. (see ADVERSE REACTIONS: Pediatric Patients).
Treatment with Lotensin is not recommended in pediatric patients less than 6 year of age (See
ADVERSE REACTIONS), and in children with glomerular filtration rate <30 mL/min as there
are insufficient data available to support a dosing recommendation in these groups. CLINICAL
PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND
ADMINISTRATION.)
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ADVERSE REACTIONS
Lotensin has been evaluated for safety in over 6000 patients with hypertension; over 700 of these
patients were treated for at least one year. The overall incidence of reported adverse events was
comparable in Lotensin and placebo patients.
The reported side effects were generally mild and transient, and there was no relation
between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg.
Discontinuation of therapy because of a side effect was required in approximately 5% of U.S.
patients treated with Lotensin and in 3% of patients treated with placebo.
The most common reasons for discontinuation were headache (0.6%) and cough (0.5%)
(see PRECAUTIONS, Cough).
The side effects considered possibly or probably related to study drug that occurred in
U.S. placebo-controlled trials in more than 1% of patients treated with Lotensin are shown
below.
PATIENTS IN U.S. PLACEBO-CONTROLLED STUDIES
LOTENSIN
PLACEBO
(N=964)
(N=496)
N
%
N
%
Headache
60
6.2
21
4.2
Dizziness
35
3.6
12
2.4
Fatigue
23
2.4
11
2.2
Somnolence
15
1.6
2
0.4
Postural Dizziness
14
1.5
1
0.2
Nausea
13
1.3
5
1.0
Cough
12
1.2
5
1.0
Other adverse experiences reported in controlled clinical trials (in less than 1% of
benazepril patients), and rarer events seen in postmarketing experience, include the following (in
some, a causal relationship to drug use is uncertain):
Cardiovascular: Symptomatic hypotension was seen in 0.3% of patients, postural hypotension
in 0.4%, and syncope in 0.1%; these reactions led to discontinuation of therapy in 4 patients who
had received benazepril monotherapy and in 9 patients who had received benazepril with
hydrochlorothiazide (see PRECAUTIONS and WARNINGS). Other reports included angina
pectoris, palpitations, and peripheral edema.
Renal: Of hypertensive patients with no apparent preexisting renal disease, about 2% have
sustained increases in serum creatinine to at least 150% of their baseline values while receiving
Lotensin, but most of these increases have disappeared despite continuing treatment. A much
smaller fraction of these patients (less than 0.1%) developed simultaneous (usually transient)
increases in blood urea nitrogen and serum creatinine.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Angioedema: Angioedema has been reported in patients receiving ACE inhibitors. During
clinical trials in hypertensive patients with benazepril, 0.5% of patients experienced edema of the
lips or face without other manifestations of angioedema. Angioedema associated with laryngeal
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edema and/or shock may be fatal. If angioedema of the face, extremities, lips, tongue, or glottis
and/or larynx occurs, treatment with Lotensin should be discontinued and appropriate therapy
instituted immediately (see WARNINGS).
Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions
(manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
Gastrointestinal: Pancreatitis, constipation, gastritis, vomiting, and melena.
Hematologic: Thrombocytopenia and hemolytic anemia.
Neurologic and Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and
paresthesia.
Other: Asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, infection, arthritis,
impotence, alopecia, arthralgia, myalgia, asthenia, and sweating.
Another potentially important adverse experience, eosinophilic pneumonitis, has been
attributed to other ACE inhibitors.
Pediatric Patients: The adverse experience profile for pediatric patients appears to be similar to
that seen in adult patients. Infants below the age of 1 year should not be given ACE inhibitors
due to concerns over possible effects on kidney development.
The long-term effects of benazepril on growth and development have not been studied.
Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Of hypertensive patients with no apparent preexisting
renal disease, about 2% have sustained increases in serum creatinine to at least 150% of their
baseline values while receiving Lotensin, but most of these increases have disappeared despite
continuing treatment. A much smaller fraction of these patients (less than 0.1%) developed
simultaneous (usually transient) increases in blood urea nitrogen and serum creatinine. None of
these increases required discontinuation of treatment. Increases in these laboratory values are
more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and,
based on experience with other ACE inhibitors, would be expected to be especially likely in
patients with renal artery stenosis (see PRECAUTIONS, General).
Potassium: Since benazepril decreases aldosterone secretion, elevation of serum potassium can
occur. Potassium supplements and potassium-sparing diuretics should be given with caution,
and the patient’s serum potassium should be monitored frequently (see PRECAUTIONS).
Hemoglobin: Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare,
occurring in only 1 of 2014 patients receiving Lotensin alone and in 1 of 1357 patients receiving
Lotensin plus a diuretic. No U.S. patients discontinued treatment because of decreases in
hemoglobin.
Other (causal relationships unknown): Clinically important changes in standard laboratory
tests were rarely associated with Lotensin administration. Elevations of uric acid, blood glucose,
serum bilirubin, and liver enzymes (see WARNINGS) have been reported, as have scattered
incidents of hyponatremia, electrocardiographic changes, leukopenia, eosinophilia, and
proteinuria. In U.S. trials, less than 0.5% of patients discontinued treatment because of
laboratory abnormalities.
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OVERDOSAGE
Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice. Rats,
however, tolerated single oral doses of up to 6 g/kg. Reduced activity was seen at 1 g/kg in mice
and at 5 g/kg in rats. Human overdoses of benazepril have not been reported, but the most
common manifestation of human benazepril overdosage is likely to be hypotension.
Laboratory determinations of serum levels of benazepril and its metabolites are not
widely available, and such determinations have, in any event, no established role in the
management of benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the
pH of the urine) that might accelerate elimination of benazepril and its metabolites. Benazepril
is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely
impaired renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Hypertension
Adults
The recommended initial dose for patients not receiving a diuretic is 10 mg once-a-day. The
usual maintenance dosage range is 20-40 mg per day administered as a single dose or in two
equally divided doses. A dose of 80 mg gives an increased response, but experience with this
dose is limited. The divided regimen was more effective in controlling trough (pre-dosing)
blood pressure than the same dose given as a once-daily regimen. Dosage adjustment should be
based on measurement of peak (2-6 hours after dosing) and trough responses. If a once-daily
regimen does not give adequate trough response, an increase in dosage or divided administration
should be considered. If blood pressure is not controlled with Lotensin alone, a diuretic can be
added.
Total daily doses above 80 mg have not been evaluated.
Concomitant administration of Lotensin with potassium supplements, potassium salt
substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see
PRECAUTIONS).
In patients who are currently being treated with a diuretic, symptomatic hypotension
occasionally can occur following the initial dose of Lotensin. To reduce the likelihood of
hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning
therapy with Lotensin (see WARNINGS). Then, if blood pressure is not controlled with
Lotensin alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg Lotensin should be used to
avoid excessive hypotension.
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Pediatrics
In children, doses of LOTENSIN between 0.1 and 0.6 mg/kg once daily have been studied, and
doses greater than 0.1 mg/kg were shown to reduce blood pressure (see Pharmacodynamics and
Clinical Effects). Based on this, the recommended starting dose of LOTENSIN is 0.2 mg/kg
once per day as monotherapy. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not
been studied in pediatric patients.
For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg)
does not correspond to the available tablet strengths for Lotensin, follow the suspension
preparation instructions below to administer benazepril HCl as a suspension.
Treatment with Lotensin is not advised for children below the age of 6 years (see
PRECAUTIONS, PEDIATRICS) and in pediatric patients with glomerular filtration rate <30
mL, as there are insufficient data available to support a dosing recommendation in these groups.
For Hypertensive Patients with Renal Impairment: For patients with a creatinine clearance <
30 mL/min/1.73 m
2 (serum creatinine > 3 mg/dL), the recommended initial dose is 5 mg
Lotensin once daily. Dosage may be titrated upward until blood pressure is controlled or to a
maximum total daily dose of 40 mg (see WARNINGS).
Preparation of Suspension (for 150 mL of a 2.0 mg/mL suspension)
Add 75 mL of Ora-Plus®* oral suspending vehicle to an amber polyethylene terephthalate
(PET) bottle containing fifteen Lotensin® 20 mg tablets, and shake for at least 2 minutes. Allow
the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension
for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet®* oral syrup vehicle to the
bottle and shake the suspension to disperse the ingredients. The suspension should be
refrigerated at 2-8 °C (36-46 °F) and can be stored for up to 30 days in the PET bottle with a
child-resistant screw-cap closure. Shake the suspension before each use.
*trademark of Paddock Laboratories, Inc. Ora-Plus(r) contains carrageenan, calcium sulfate,
citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium,
potassium sorbate, simethicone, sodium phosphate monobasic, xanthan gum, and water. Ora-
Sweet(r) contains citric acid, berry citrus flavorant, glycerin, methylparaben, potassium sorbate,
sodium phosphate monobasic, sorbitol, sucrose, and water.
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HOW SUPPLIED
Lotensin is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in
bottles of 90 and 100 tablets. Lotensin is also supplied in blister packages (1 tablet/blister), in
Accu-Pak
® Unit Dose boxes containing 10 strips of 10 blisters each.
Each tablet is imprinted with LOTENSIN on one side and the tablet strength (“5,” “10,”
“20,” or “40”) on the other.
The National Drug Codes for the various packages are
Tablet
Dose
Color
Bottle of 90
Bottle of 100
Accu-Pak® of 100
5 mg
light yellow
NDC 0083-0059-90
NDC 0083-0059-30
NDC 0083-0059-32
10 mg
dark yellow
NDC 0083-0063-90
NDC 0083-0063-30
NDC 0083-0063-32
20 mg
pink
NDC 0083-0079-90
NDC 0083-0079-30
NDC 0083-0079-32
40 mg
dark rose
NDC 0083-0094-90
NDC 0083-0094-30
NDC 0083-0094-32
Storage: Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
T2002-06
REV: JANUARY 2002
Printed in U.S.A.
89008505
Manufactured by: Novartis Pharmaceuticals Corporation
Suffern, NY 10901
Distributed by: Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
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|
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2025-02-12T13:46:08.505785
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/019851s028lbl.pdf', 'application_number': 19851, 'submission_type': 'SUPPL ', 'submission_number': 28}
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Lotensin®
(benazepril hydrochloride)
Tablets
Rx only
Prescribing Information
USE IN PREGNANCY
When used in pregnancy, ACE inhibitors can cause injury and even death to the
developing fetus. When pregnancy is detected, Lotensin should be discontinued as soon as
possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Its chemical name is 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)
propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid
monohydrochloride; its structural formula is structural formula
Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting
enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril
hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide,
crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron
oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80,
propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and
animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the
Reference ID: 2960139
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vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by
the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Hypertensive patients treated with Lotensin alone for up to
52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with
Lotensin and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to
angiotensin II and did not interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin
remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive
effect even in patients with low-renin hypertension (see INDICATIONS AND USAGE).
Pharmacokinetics and Metabolism
Following oral administration of Lotensin, peak plasma concentrations of benazepril are reached
within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery
and is not significantly influenced by the presence of food in the GI tract.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite,
benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake
in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein
binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by
equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be
unaffected by age, hepatic dysfunction, or concentration (over the concentration range of
0.24-23.6 µmol/L).
Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE
inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and
benazeprilat. Only trace amounts of an administered dose of Lotensin can be recovered in the
urine as unchanged benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as
benazepril glucuronide, and 8% as benazeprilat glucuronide.
The kinetics of benazepril are approximately dose-proportional within the dosage range of
10-80 mg.
In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of
benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should
be reached after 2 or 3 doses of benazepril hydrochloride given once daily.
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The kinetics did not change, and there was no significant accumulation during chronic
administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios
based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects
with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately
11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary
clearance may compensate to an extent for deficient renal clearance.
In patients with renal insufficiency, the disposition of benazepril and benazeprilat in patients with
mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in
patients with normal renal function. In patients with creatinine clearance ≤30 mL/min, peak
benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be
delayed (see DOSAGE AND ADMINISTRATION).
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of
benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not
detected in the dialysate.
In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are
essentially unaltered. The pharmacokinetics of benazepril and benazeprilat do not appear to be
influenced by age.
In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of
Lotensin (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was
0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg
(0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The
terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third
that observed in adults.
Pharmacodynamics
Single and multiple doses of 10 mg or more of Lotensin cause inhibition of plasma ACE activity
by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous
angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.
Hypertension
Adult
Administration of Lotensin to patients with mild-to-moderate hypertension results in a reduction
of both supine and standing blood pressure to about the same extent with no compensatory
tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients
who are salt- and/or volume-depleted (see WARNINGS).
In single-dose studies, Lotensin lowered blood pressure within 1 hour, with peak reductions
achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for
24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The trough values represent
reductions of about 50% of that seen at peak.
Reference ID: 2960139
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Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate
hypertensive patients not using diuretics. The minimal effective once-daily dose of Lotensin was
10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher
doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of
Lotensin given as a single morning dose or as a twice-daily dose, blood pressure reductions at
the time of morning trough blood levels were greater with the divided regimen.
During chronic therapy, the maximum reduction in blood pressure with any dose is generally
achieved after 1-2 weeks. The antihypertensive effects of Lotensin have continued during
therapy for at least two years. Abrupt withdrawal of Lotensin has not been associated with a
rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, Lotensin 10-20 mg was similar in effectiveness
to captopril, hydrochlorothiazide, nifedipine SR, and propranolol.
The antihypertensive effects of Lotensin were not appreciably different in patients receiving
high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in
peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or
no change in heart rate. In normal human volunteers, single doses of benazepril caused an
increase in renal blood flow but had no effect on glomerular filtration rate.
Use of Lotensin in combination with thiazide diuretics gives a blood-pressure-lowering effect
greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone
axis, administration of Lotensin tends to reduce the potassium loss associated with the diuretic.
Pediatric
In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic
pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or
0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85
patients whose blood pressure was reduced on therapy were then randomized to either placebo or
benazepril and were followed up for an additional two weeks. At the end of two weeks, blood
pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg
more than in children on benazepril. No dose-response was observed for the three doses.
INDICATIONS AND USAGE
Lotensin is indicated for the treatment of hypertension. It may be used alone or in combination
with thiazide diuretics.
In using Lotensin, consideration should be given to the fact that another angiotensin-converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal
impairment or collagen-vascular disease. Available data are insufficient to show that Lotensin
does not have a similar risk (see WARNINGS).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to nonblacks. It should also be noted that in controlled clinical trials ACE
inhibitors have an effect on blood pressure that is less in black patients than in nonblacks.
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CONTRAINDICATIONS
Lotensin is contraindicated in patients who are hypersensitive to this product or to any other
ACE inhibitor.
Lotensin is also contraindicated in patients with a history of angioedema with or without
previous ACE inhibitor treatment.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including Lotensin) may be subject to a variety of adverse reactions, some of them
serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In
U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who
received placebo and in about 0.5% of the subjects who received Lotensin. Angioedema
associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, treatment with Lotensin should be discontinued and appropriate therapy
instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to
cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection
1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see ADVERSE
REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not
approved in the United States).
Hypotension
Lotensin can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has been
only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic
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hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a
result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.
Volume-and/or salt-depletion should be corrected before initiating therapy with Lotensin.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or
azotemia and, rarely, with acute renal failure and death. In such patients, Lotensin therapy should
be started under close medical supervision; they should be followed closely for the first 2 weeks
of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated
with intravenous infusion of physiological saline. Lotensin treatment usually can be continued
following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more
frequently in patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials
of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar
rates. Monitoring of white blood cell counts should be considered in patients with collagen-
vascular disease, especially if the disease is associated with impaired renal function.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant
women. Several dozen cases have been reported in the world literature. When pregnancy is
detected, Lotensin should be discontinued as soon as possible and monitoring of the fetal
development should be performed on a regular basis.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE inhibitor exposure.
In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated
with a potentially increased risk of birth defects. In women planning to become pregnant, ACE
inhibitors (including Lotensin) should not be used. Women of childbearing age should be made
aware of the potential risk and ACE inhibitors (including Lotensin) should only be given after
careful counseling and consideration of individual risks and benefits.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
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If oligohydramnios is observed, benazepril should be discontinued unless it is considered life
saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as means of reversing hypotension and/or substituting for disordered renal function. Benazepril,
which crosses the placenta, can theoretically be removed from the neonatal circulation by these
means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor,
but experience is limited.
No teratogenic effects of Lotensin were seen in studies of pregnant rats, mice, and rabbits. On a
mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more
than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman).
On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3
times (in rabbits) the maximum recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors,
including Lotensin, may be associated with oliguria and/or progressive azotemia and (rarely)
with acute renal failure and/or death. In a small study of hypertensive patients with renal artery
stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with Lotensin was
associated with increases in blood urea nitrogen and serum creatinine; these increases were
reversible upon discontinuation of Lotensin or diuretic therapy, or both. When such patients are
treated with ACE inhibitors, renal function should be monitored during the first few weeks of
therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have
developed increases in blood urea nitrogen and serum creatinine, usually minor and transient,
especially when Lotensin has been given concomitantly with a diuretic. This is more likely to
occur in patients with preexisting renal impairment. Dosage reduction of Lotensin and/or
discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should
always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
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Hyperkalemia: In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater than
the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving
Lotensin. In most cases, these were isolated values which resolved despite continued therapy.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with Lotensin
(see Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Impaired Liver Function: In patients with hepatic dysfunction due to cirrhosis, levels of
benazeprilat are essentially unaltered (see WARNINGS, Hepatic Failure).
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that
produce hypotension, benazepril will block the angiotensin II formation that could otherwise
occur secondary to compensatory renin release. Hypotension that occurs as a result of this
mechanism can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACE inhibitors. Discuss other treatment options with women planning to become
pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. Patients should be so advised and told to report immediately any signs or
symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in
breathing) and to take no more drug until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first days of therapy, and it should be reported to the prescribing physician.
Patients should be told that if syncope occurs, Lotensin should be discontinued until the
prescribing physician has been consulted.
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure, with the same consequences of
lightheadedness and possible syncope.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting the prescribing physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia.
Drug Interactions
Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently
instituted, may occasionally experience an excessive reduction of blood pressure after initiation
of therapy with Lotensin. The possibility of hypotensive effects with Lotensin can be minimized
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by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment
with Lotensin. If this is not possible, the starting dose should be reduced (see DOSAGE AND
ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: Lotensin can attenuate potassium
loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride,
triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.
Therefore, if concomitant use of such agents is indicated, they should be given with caution, and
the patient’s serum potassium should be monitored frequently.
Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify any
clinically important effects on the serum concentrations or clinical effects of these
anticoagulants.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors (including benazepril) during therapy with lithium. These
drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is
recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Anti-diabetics: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril)
concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients
should therefore be advised about the possibility of hypoglycemic reactions and should be
monitored accordingly.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible
acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving benazepril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.
Other: No clinically important pharmacokinetic interactions occurred when Lotensin was
administered concomitantly with hydrochlorothiazide, chlorthalidone, furosemide, digoxin,
propranolol, atenolol, or cimetidine.
Lotensin has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel
blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important
adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive effects
with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting
parts of the renin-angiotensin system.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was administered to rats and mice for
up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights,
this dose is 110 times the maximum recommended human dose. When compared on the basis of
body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum
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recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic
activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in
vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. In
doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on
mg/m
2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg
comparison), Lotensin had no adverse effect on the reproductive performance of male and
female rats.
Pregnancy Category D
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk
of lactating women treated with benazepril. A newborn child ingesting entirely breast milk
would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.
Geriatric Use
Of the total number of patients who received benazepril in U.S. clinical studies of Lotensin, 18%
were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety
were observed between these patients and younger patients, and other reported clinical
experience has not identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Pediatric Use
The antihypertensive effects of Lotensin have been evaluated in a double-blind study in pediatric
patients 7 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics,
Hypertension). The pharmacokinetics of Lotensin have been evaluated in pediatric patients 6 to
16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism).
Lotensin was generally well tolerated and adverse effects were similar to those described in
adults. (See ADVERSE REACTIONS: Pediatric Patients).
Treatment with Lotensin is not recommended in pediatric patients less than 6 years of age (see
ADVERSE REACTIONS), and in children with glomerular filtration rate <30 mL/min as there
are insufficient data available to support a dosing recommendation in these groups. (See
CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism, In Pediatric Patients and
DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Lotensin has been evaluated for safety in over 6000 patients with hypertension; over 700 of these
patients were treated for at least one year. The overall incidence of reported adverse events was
comparable in Lotensin and placebo patients.
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The reported side effects were generally mild and transient, and there was no relation between
side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg.
Discontinuation of therapy because of a side effect was required in approximately 5% of U.S.
patients treated with Lotensin and in 3% of patients treated with placebo.
The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) (see
PRECAUTIONS, Cough).
The side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in more than 1% of patients treated with Lotensin are shown below.
PATIENTS IN U.S. PLACEBO-CONTROLLED STUDIES
LOTENSIN
PLACEBO
(N=964)
(N=496)
N
%
N
%
Headache
60
6.2
21
4.2
Dizziness
35
3.6
12
2.4
Fatigue
23
2.4
11
2.2
Somnolence
15
1.6
2
0.4
Postural Dizziness
14
1.5
1
0.2
Nausea
13
1.3
5
1.0
Cough
12
1.2
5
1.0
Other adverse experiences reported in controlled clinical trials (in less than 1% of benazepril
patients), and rarer events seen in post-marketing experience, include the following (in some, a
causal relationship to drug use is uncertain):
Cardiovascular: Symptomatic hypotension was seen in 0.3% of patients, postural hypotension
in 0.4%, and syncope in 0.1%; these reactions led to discontinuation of therapy in 4 patients who
had received benazepril monotherapy and in 9 patients who had received benazepril with
hydrochlorothiazide (see PRECAUTIONS and WARNINGS). Other reports included angina
pectoris, palpitations, and peripheral edema.
Renal: Of hypertensive patients with no apparent preexisting renal disease, about 2% have
sustained increases in serum creatinine to at least 150% of their baseline values while receiving
Lotensin, but most of these increases have disappeared despite continuing treatment. A much
smaller fraction of these patients (less than 0.1%) developed simultaneous (usually transient)
increases in blood urea nitrogen and serum creatinine.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Angioedema: Angioedema has been reported in patients receiving ACE inhibitors. During
clinical trials in hypertensive patients with benazepril, 0.5% of patients experienced edema of the
lips or face without other manifestations of angioedema. Angioedema associated with laryngeal
edema and/or shock may be fatal. If angioedema of the face, extremities, lips, tongue, or glottis
and/or larynx occurs, treatment with Lotensin should be discontinued and appropriate therapy
instituted immediately (see WARNINGS).
Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions
(manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
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Gastrointestinal: Pancreatitis, constipation, gastritis, vomiting, and melena.
Hematologic: Thrombocytopenia and hemolytic anemia.
Neurologic and Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and
paresthesia.
Other: Asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination,
infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, and sweating.
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed
to other ACE inhibitors.
The following adverse events of unknown frequency have been reported during post-marketing
use of benazepril: small bowel angioedema, anaphylactoid reactions, hyperkalemia,
agranulocytosis, and neutropenia.
Pediatric Patients: The adverse experience profile for pediatric patients appears to be similar to
that seen in adult patients. Infants below the age of 1 year should not be given ACE inhibitors
due to concerns over possible effects on kidney development.
The long-term effects of benazepril on growth and development have not been studied.
Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Of hypertensive patients with no apparent preexisting
renal disease, about 2% have sustained increases in serum creatinine to at least 150% of their
baseline values while receiving Lotensin, but most of these increases have disappeared despite
continuing treatment. A much smaller fraction of these patients (less than 0.1%) developed
simultaneous (usually transient) increases in blood urea nitrogen and serum creatinine. None of
these increases required discontinuation of treatment. Increases in these laboratory values are
more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and,
based on experience with other ACE inhibitors, would be expected to be especially likely in
patients with renal artery stenosis (see PRECAUTIONS, General).
Potassium: Since benazepril decreases aldosterone secretion, elevation of serum potassium can
occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and
the patient’s serum potassium should be monitored frequently (see PRECAUTIONS).
Hemoglobin: Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare,
occurring in only 1 of 2,014 patients receiving Lotensin alone and in 1 of 1,357 patients
receiving Lotensin plus a diuretic. No U.S. patients discontinued treatment because of decreases
in hemoglobin.
Other (causal relationships unknown): Clinically important changes in standard laboratory
tests were rarely associated with Lotensin administration. Elevations of uric acid, blood glucose,
serum bilirubin, and liver enzymes (see WARNINGS) have been reported, as have scattered
incidents of hyponatremia, electrocardiographic changes, leukopenia, eosinophilia, and
proteinuria. In U.S. trials, less than 0.5% of patients discontinued treatment because of laboratory
abnormalities.
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OVERDOSAGE
Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice. Rats,
however, tolerated single oral doses of up to 6 g/kg. Reduced activity was seen at 1 g/kg in mice
and at 5 g/kg in rats. Human overdoses of benazepril have not been reported, but the most
common manifestation of human benazepril overdosage is likely to be hypotension.
Laboratory determinations of serum levels of benazepril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of
the urine) that might accelerate elimination of benazepril and its metabolites. Benazepril is only
slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired
renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Hypertension
Adults
The recommended initial dose for patients not receiving a diuretic is 10 mg once a day. The
usual maintenance dosage range is 20-40 mg per day administered as a single dose or in two
equally divided doses. A dose of 80 mg gives an increased response, but experience with this
dose is limited. The divided regimen was more effective in controlling trough (pre-dosing) blood
pressure than the same dose given as a once-daily regimen. Dosage adjustment should be based
on measurement of peak (2-6 hours after dosing) and trough responses. If a once-daily regimen
does not give adequate trough response, an increase in dosage or divided administration should
be considered. If blood pressure is not controlled with Lotensin alone, a diuretic can be added.
Total daily doses above 80 mg have not been evaluated.
Concomitant administration of Lotensin with potassium supplements, potassium salt substitutes,
or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS).
In patients who are currently being treated with a diuretic, symptomatic hypotension
occasionally can occur following the initial dose of Lotensin. To reduce the likelihood of
hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning
therapy with Lotensin (see WARNINGS). Then, if blood pressure is not controlled with Lotensin
alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg Lotensin should be used to avoid
excessive hypotension.
Pediatrics
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In children, doses of Lotensin between 0.1 and 0.6 mg/kg once daily have been studied, and
doses greater than 0.1 mg/kg were shown to reduce blood pressure (see Pharmacodynamics).
Based on this, the recommended starting dose of Lotensin is 0.2 mg/kg once per day as
monotherapy. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in
pediatric patients.
For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg)
does not correspond to the available tablet strengths for Lotensin, follow the suspension
preparation instructions below to administer benazepril HCl as a suspension.
Treatment with Lotensin is not advised for children below the age of 6 years (see
PRECAUTIONS, Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL,
as there are insufficient data available to support a dosing recommendation in these groups.
For Hypertensive Patients with Renal Impairment
For patients with a creatinine clearance <30 mL/min/1.73 m
2 (serum creatinine >3 mg/dL), the
recommended initial dose is 5 mg Lotensin once daily. Dosage may be titrated upward until
blood pressure is controlled or to a maximum total daily dose of 40 mg (see WARNINGS).
Preparation of Suspension (for 150 mL of a 2 mg/mL suspension)
Add 75 mL of Ora-Plus®* oral suspending vehicle to an amber polyethylene terephthalate (PET)
bottle containing fifteen Lotensin 20 mg tablets, and shake for at least 2 minutes. Allow the
suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a
minimum of 1 additional minute. Add 75 mL of Ora-Sweet®* oral syrup vehicle to the bottle and
shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C
(36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap
closure. Shake the suspension before each use.
*Ora-Plus® and Ora-Sweet® are registered trademarks of Paddock Laboratories, Inc. Ora-Plus®
contains carrageenan, citric acid, methylparaben, microcrystalline cellulose,
carboxymethylcellulose sodium, potassium sorbate, simethicone, sodium phosphate monobasic,
xanthan gum, and water. Ora-Sweet® contains citric acid, berry citrus flavorant, glycerin,
methylparaben, potassium sorbate, sodium phosphate monobasic, sorbitol, sucrose, and water.
HOW SUPPLIED
Lotensin is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in
bottles of 100 tablets.
Each tablet is imprinted with LOTENSIN on one side and the tablet strength (“5,” “10,” “20,” or
“40”) on the other.
The National Drug Codes for the various packages are
Tablet
Dose
Color
Bottle of 100
5 mg
light yellow
NDC 0078-0447-05
10 mg
dark yellow
NDC 0078-0448-05
20 mg
pink
NDC 0078-0449-05
40 mg
dark rose
NDC 0078-0450-05
Reference ID: 2960139
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage: Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
T2011-56
May 2011 company logo
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
Reference ID: 2960139
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:08.568817
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019851s040lbl.pdf', 'application_number': 19851, 'submission_type': 'SUPPL ', 'submission_number': 40}
|
11,781
|
78732XX
NDA 19-853 Cuprimine/S-012 & 014
Page 1
CAPSULES
CUPRIMINE®
(PENICILLAMINE)
Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special
dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient
should remain constantly under the close supervision of the physician. Patients should be warned to report
promptly any symptoms suggesting toxicity.
DESCRIPTION
Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine
excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional
therapy (see INDICATIONS). It is 3-mercapto-D-valine. It is a white or practically white, crystalline powder,
freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon
tetrachloride. Although its configuration is D, it is levorotatory as usually measured:
[α] 25°
= -62.5° ± 2° (c = 1, 1N NaOH),
D
calculated on a dried basis.
The empirical formula is C5H11NO2S, giving it a molecular weight of 149.21. The structural formula is:
It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid.
Capsules CUPRIMINE* (Penicillamine) for oral administration contain either 125 mg or 250 mg of
penicillamine. Each capsule contains the following inactive ingredients: D & C Yellow 10, gelatin, lactose,
magnesium stearate, and titanium dioxide. The 125 mg capsule also contains iron oxide.
CLINICAL PHARMACOLOGY
Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's
disease. From in vitro studies which indicate that one atom of copper combines with two molecules of
penicillamine, it would appear that one gram of penicillamine should be followed by the excretion of about 200
milligrams of copper; however, the actual amount excreted is about one percent of this.
Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide
interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a
substance that is much more soluble than cystine and is excreted readily.
Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them
when newly formed.
The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress
disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but
produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic
immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.
In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity
to its effect in rheumatoid arthritis is not known.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1985, 1989,1992
All rights reserved
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CUPRIMINE® (Penicillamine)
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In rheumatoid arthritis, the onset of therapeutic response to CUPRIMINE may not be seen for two or three
months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain,
tenderness, and swelling is generally apparent within three months. The optimum duration of therapy has not
been determined. If remissions occur, they may last from months to years, but usually require continued
treatment (see DOSAGE AND ADMINISTRATION).
In all patients receiving penicillamine, it is important that CUPRIMINE be given on an empty stomach, at
least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food,
milk, antacid, zinc or iron-containing preparation. This permits maximum absorption and reduces the likelihood
of inactivation by metal binding in the gastrointestinal tract.
Pharmacokinetics
Penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide inter-
individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of
penicillamine occurs 1-3 hours after ingestion; it is approximately 1-2 mg/L after an oral dose of 250 mg. The
drug appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide.
When prolonged treatment is stopped, there is a slow elimination phase lasting 4-6 days.
More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug
also binds to erythrocytes and macrophages. A small fraction of the dose is metabolized in the liver to S-methyl-
D-penicillamine. Excretion is mainly renal, mainly as disulfides.
INDICATIONS
CUPRIMINE is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active
rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence
suggests that CUPRIMINE is not of value in ankylosing spondylitis.
Wilson’s Disease — Wilson’s disease (hepatolenticular degeneration) occurs in individuals who have
inherited an autosomal recessive defect that leads to an accumulation of copper far in excess of metabolic
requirements. The excess copper is deposited in several organs and tissues, and eventually produces
pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain,
where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown
Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are
either asymptomatic or manifest only hepatic symptomatology.
Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic
in whom it can be assumed the disease will develop in the future if the patient is not treated.
The diagnosis, if suspected on the basis of family or individual history or physical examination, can be
confirmed if the plasma copper-protein ceruloplasmin** is <20 mg/dL and either a quantitative determination in a
liver biopsy specimen shows an abnormally high concentration of copper (>250 mcg/g dry weight) or Kayser-
Fleischer rings are present.
Treatment has two objectives:
(1) to minimize dietary intake of copper;
(2) to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.
The first objective is attained by a daily diet that contains no more than one or two milligrams of copper. Such
a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and
cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of
foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water
contains more than 0.1 mg of copper per liter.
For the second objective, a copper chelating agent is used.
In symptomatic patients this treatment usually produces marked neurologic improvement, fading of Kayser-
Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.
Clinical experience to date suggests that life is prolonged with the above regimen.
Noticeable improvement may not occur for one to three months. Occasionally, neurologic symptoms become
worse during initiation of therapy with CUPRIMINE. Despite this, the drug should not be withdrawn. Temporary
** For quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I.; Scheinberg, I.H.: Measurement of the concentration of
ceruloplasmin in serum by determination of its oxidase activity, in “Laboratory Diagnosis of Liver Disease”, F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St.
Louis, Warren H. Green, Inc., 1968, pp. 193-195.
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interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it
may result in clinical improvement of neurological symptoms (see WARNINGS). If the neurological symptoms
and signs continue to worsen for a month after the initiation of CUPRIMINE therapy, several short courses of
treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE may be considered.
Treatment of asymptomatic patients has been carried out for over thirty years. Symptoms and signs of the
disease appear to be prevented indefinitely if daily treatment with CUPRIMINE is continued.
Cystinuria — Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine,
lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that
leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is
influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular
dysfunction.
Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent
pathology connected with their excretion in excessive quantities.
Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so
crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria.
Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed
1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is
indicated.
Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation,
keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by
a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine
specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in
methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy
because of its low protein content (see PRECAUTIONS).
When these measures are inadequate to control recurrent stone formation, CUPRIMINE may be used as
additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE may be a useful
substitute. It is capable of keeping cystine excretion to near normal values, thereby hindering stone formation
and the serious consequences of pyelonephritis and impaired renal function that develop in some patients.
Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-
cysteine mixed disulfide as:
CSSC + PS′
CS′ + CSSP
PSSP + CS′
PS′ + CSSP
CSSC + PSSP′
2CSSP
CSSC = cystine
CS′ = deprotonated cysteine
PSSP = penicillamine disulfide
PS′ = deprotonated penicillamine sulfhydryl
CSSP = penicillamine-cysteine mixed disulfide
In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing
about the disulfide interchange.
Rheumatoid Arthritis — Because CUPRIMINE can cause severe adverse reactions, its use in rheumatoid
arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an
adequate trial of conventional therapy. Even then, benefit-to-risk ratio should be carefully considered. Other
measures, such as rest, physiotherapy, salicylates, and corticosteroids should be used, when indicated, in
conjunction with CUPRIMINE (see PRECAUTIONS).
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CUPRIMINE® (Penicillamine)
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CONTRAINDICATIONS
Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during
pregnancy is contraindicated (see WARNINGS).
Although breast milk studies have not been reported in animals or humans, mothers on therapy with
penicillamine should not nurse their infants.
Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on
penicillamine (see WARNINGS and ADVERSE REACTIONS).
Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid
arthritis patients with a history or other evidence of renal insufficiency.
WARNINGS
The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia,
agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.
Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine
urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be
done twice weekly, together with monitoring of the patient's skin, lymph nodes and body temperature, during the
first month of therapy, every two weeks for the next five months, and monthly thereafter. Patients should be
instructed to report promptly the development of signs and symptoms of granulocytopenia and/or
thrombocytopenia such as fever, sore throat, chills, bruising or bleeding. The above laboratory studies should
then be promptly repeated.
Leukopenia and thrombocytopenia have been reported to occur in up to five percent of patients during
penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an
increase in eosinophils. A confirmed reduction in WBC below 3500/mm3 mandates discontinuance of
penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent
megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is
presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be
normal or sometimes increased. The development of a platelet count below 100,000/mm3, even in the absence
of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either
platelet count or WBC in three successive determinations, even though values are still within the normal range,
likewise requires at least temporary cessation.
Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous
glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In
some patients the proteinuria disappears with continued therapy; in others, penicillamine must be discontinued.
When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-
induced glomerulopathy or is unrelated to penicillamine.
Rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on
penicillamine therapy, provided that quantitative 24-hour urinary protein determinations are obtained at intervals
of one to two weeks. Penicillamine dosage should not be increased under these circumstances. Proteinuria
which exceeds 1 g/24 hours, or proteinuria which is progressively increasing, requires either discontinuance of
the drug or a reduction in the dosage. In some patients, proteinuria has been reported to clear following
reduction in dosage.
In rheumatoid arthritis patients penicillamine should be discontinued if unexplained gross hematuria or
persistent microscopic hematuria develops.
In patients with Wilson's disease or cystinuria the risks of continued penicillamine therapy in patients
manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits.
When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. Cystine stones form
rapidly, sometimes in six months.
Up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has
been discontinued.
Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended
every six months for the duration of therapy. In Wilson’s disease, these are recommended every three months,
at least during the first year of treatment.
Goodpasture's syndrome has occurred rarely. The development of abnormal urinary findings associated with
hemoptysis and pulmonary infiltrates on x-ray requires immediate cessation of penicillamine.
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CUPRIMINE® (Penicillamine)
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Obliterative bronchiolitis has been reported rarely. The patient should be cautioned to report immediately
pulmonary symptoms such as exertional dyspnea, unexplained cough or wheezing. Pulmonary function studies
should be considered at that time.
Onset of new neurological symptoms has been reported with CUPRIMINE (see ADVERSE REACTIONS).
Occasionally, neurological symptoms become worse during initiation of therapy with CUPRIMINE (see
INDICATIONS). Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis
and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of
cases, symptoms of myasthenia have receded after withdrawal of penicillamine.
Most of the various forms of pemphigus have occurred during treatment with penicillamine. Pemphigus
vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. The
seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. When pemphigus is
suspected, CUPRIMINE should be discontinued. Treatment has consisted of high doses of corticosteroids alone
or, in some cases, concomitantly with an immunosuppressant. Treatment may be required for only a few weeks
or months, but may need to be continued for more than a year.
Once instituted for Wilson's disease or cystinuria, treatment with penicillamine should, as a rule, be
continued on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after
reinstitution of therapy.
Pregnancy Category D
Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine has been shown
to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human
use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.
There are no controlled studies on the use of penicillamine in pregnant women. Although normal outcomes
have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in
infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should be used
in women of childbearing potential only when the expected benefits outweigh the possible hazards. Women on
therapy with penicillamine who are of childbearing potential should be apprised of this risk, advised to report
promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early
recognition of pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard to the fetus.
Wilson's Disease — Reported experience*** shows that continued treatment with penicillamine throughout
pregnancy protects the mother against relapse of the Wilson's disease, and that discontinuation of penicillamine
has deleterious effects on the mother, which may be fatal.
If penicillamine is administered during pregnancy to patients with Wilson's disease, it is recommended that
the daily dosage be limited to 750 mg. If cesarean section is planned the daily dose should be reduced to
250 mg, but not lower, for the last six weeks of pregnancy and postoperatively until wound healing is complete.
Cystinuria — If possible, penicillamine should not be given during pregnancy to women with cystinuria (see
CONTRAINDICATIONS). There are reports of women with cystinuria on therapy with penicillamine who gave
birth to infants with generalized connective tissue defects who died following abdominal surgery. If stones
continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the
fetus.
Rheumatoid Arthritis — Penicillamine should not be administered to rheumatoid arthritis patients who are
pregnant (see CONTRAINDICATIONS) and should be discontinued promptly in patients in whom pregnancy is
suspected or diagnosed.
There is a report that a woman with rheumatoid arthritis treated with less than one gram a day of
penicillamine during pregnancy gave birth (cesarean delivery) to an infant with growth retardation, flattened face
with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin.
PRECAUTIONS
Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second
to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous
eruption.
In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily
discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is
*** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med. 293: 1300-1302, Dec. 18, 1975.
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gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is
usually helpful, in such patients in whom drug fever and rash develop several times.
In the case of drug fever in rheumatoid arthritis patients, because other treatments are available,
penicillamine should be discontinued and another therapeutic alternative tried since experience indicates that
the febrile reaction will recur in a very high percentage of patients upon readministration of penicillamine.
The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have
occurred. Early rash occurs during the first few months of treatment and is more common. It is usually a
generalized pruritic, erythematous, maculopapular or morbilliform rash and resembles the allergic rash seen
with other drugs. Early rash usually disappears within days after stopping penicillamine and seldom recurs when
the drug is restarted at a lower dosage. Pruritus and early rash may often be controlled by the concomitant
administration of antihistamines. Less commonly, a late rash may be seen, usually after six months or more of
treatment, and requires discontinuation of penicillamine. It is usually on the trunk, is accompanied by intense
pruritus, and is usually unresponsive to topical corticosteroid therapy. Late rash may take weeks to disappear
after penicillamine is stopped and usually recurs if the drug is restarted.
The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic
manifestations usually requires discontinuation of penicillamine.
Certain patients will develop a positive antinuclear antibody (ANA) test and some of these may show a lupus
erythematosus-like syndrome similar to drug-induced lupus associated with other drugs. The lupus
erythematosus-like syndrome is not associated with hypocomplementemia and may be present without
nephropathy. The development of a positive ANA test does not mandate discontinuance of the drug; however,
the physician should be alerted to the possibility that a lupus erythematosus-like syndrome may develop in the
future.
Some patients may develop oral ulcerations which in some cases have the appearance of aphthous
stomatitis. The stomatitis usually recurs on rechallenge but often clears on a lower dosage. Although rare,
cheilosis, glossitis and gingivostomatitis have also been reported. These oral lesions are frequently dose-related
and may preclude further increase in penicillamine dosage or require discontinuation of the drug.
Hypogeusia (a blunting or diminution in taste perception) has occurred in some patients. This may last two to
three months or more and may develop into a total loss of taste; however, it is usually self-limited despite
continued penicillamine treatment. Such taste impairment is rare in patients with Wilson's disease.
Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or
cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar
serious hematologic and renal adverse reactions. Patients who have had gold salt therapy discontinued due to a
major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of
the same type.
Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine. The possibility
of reactions from contamination of penicillamine by trace amounts of penicillin has been eliminated now that
penicillamine is being produced synthetically rather than as a degradation product of penicillin.
Patients with Wilson’s disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since
penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin
preparation, although there is no evidence that deficiency of any vitamin other than pyridoxine is associated with
penicillamine. In Wilson's disease, multivitamin preparations must be copper-free.
Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of
pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
Iron deficiency may develop, especially in pediatric patients and in menstruating women. In Wilson's disease,
this may be a result of adding the effects of the low copper diet, which is probably also low in iron, and the
penicillamine to the effects of blood loss or growth. In cystinuria, a low methionine diet may contribute to iron
deficiency, since it is necessarily low in protein. If necessary, iron may be given in short courses, but a period of
two hours should elapse between administration of penicillamine and iron, since orally administered iron has
been shown to reduce the effects of penicillamine.
Penicillamine causes an increase in the amount of soluble collagen. In the rat this results in inhibition of
normal healing and also a decrease in tensile strength of intact skin. In man this may be the cause of increased
skin friability at sites especially subject to pressure or trauma, such as shoulders, elbows, knees, toes, and
buttocks. Extravasations of blood may occur and may appear as purpuric areas, with external bleeding if the
skin is broken, or as vesicles containing dark blood. Neither type is progressive. There is no apparent
association with bleeding elsewhere in the body and no associated coagulation defect has been found. Therapy
with penicillamine may be continued in the presence of these lesions. They may not recur if dosage is reduced.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
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Other reported effects probably due to the action of penicillamine on collagen are excessive wrinkling of the skin
and development of small, white papules at venipuncture and surgical sites.
The effects of penicillamine on collagen and elastin make it advisable to consider a reduction in dosage to
250 mg/day, when surgery is contemplated. Reinstitution of full therapy should be delayed until wound healing is
complete.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that five of
ten autoimmune disease-prone NZB hybrid mice developed lymphocytic leukemia after 6 months' intraperitoneal
treatment with a dose of 400 mg/kg penicillamine 5 days per week.
Penicillamine is directly mutagenic to S. typhimurium strain TA92 in the Ames test; mutagenicity is enhanced
by kidney postmitochondrial subcellular fraction 9. Penicillamine does not induce gene mutations in Chinese
hamster V79 cells.
Penicillamine induces sister-chromatid exchanges and chromosome aberrations in cultivated mammalian
cells.No studies on the effect of penicillamine on fertility are available.
Pregnancy
Pregnancy Category D
(see WARNINGS, Pregnancy)
Nursing Mothers
See CONTRAINDICATIONS.
Pediatric Use
The efficacy of CUPRIMINE in juvenile rheumatoid arthritis has not been established.
Geriatric Use
Clinical studies of CUPRIMINE are limited in subjects aged 65 and over, they did not include sufficient
numbers of elderly subjects aged 65 and over to adequately determine whether they respond differently from
younger subjects. Review of reported clinical trials with penicillamine in the elderly suggest greater risk than in
younger patients for overall skin rash and abnormality of taste. In general, dose selection for an elderly patient
should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal or cardiac function, and of concomitant disease or other drugs.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may
be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and careful monitoring of renal function is recommended.
ADVERSE REACTIONS
Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervision
throughout the period of drug administration (see WARNINGS and PRECAUTIONS).
Reported incidences (%) for the most commonly occurring adverse reactions in rheumatoid arthritis patients
are noted, based on 17 representative clinical trials reported in the literature (1270 patients).
Allergic — Generalized pruritus, early and late rashes (5%), pemphigus (see WARNINGS), and drug
eruptions which may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see WARNINGS
and PRECAUTIONS). Some patients may show a lupus erythematosus-like syndrome similar to drug-induced
lupus produced by other pharmacological agents (see PRECAUTIONS).
Urticaria and exfoliative dermatitis have occurred.
Thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported.
These reactions are extremely rare.
Some patients may develop a migratory polyarthralgia, often with objective synovitis (see DOSAGE AND
ADMINISTRATION).
Gastrointestinal — Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%).
Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction including hepatic
failure, and pancreatitis. Intrahepatic cholestasis and toxic hepatitis have been reported rarely. There have been
a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation
and thymol turbidity tests.
Some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral
ulcerations. Although rare, cheilosis, glossitis, and gingivostomatitis have been reported (see PRECAUTIONS).
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Gastrointestinal side effects are usually reversible following cessation of therapy.
Hematological — Penicillamine can cause bone marrow depression (see WARNINGS). Leukopenia (2%)
and thrombocytopenia (4%) have occurred. Fatalities have been reported as a result of thrombocytopenia,
agranulocytosis, aplastic anemia, and sideroblastic anemia.
Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis,
eosinophilia, and thrombocytosis have also been reported.
Renal — Patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some,
may progress to the development of the nephrotic syndrome as a result of an immune complex membranous
glomerulopathy (see WARNINGS). Renal failure has been reported.
Central Nervous System — Tinnitus, optic neuritis and peripheral sensory and motor neuropathies (including
polyradiculoneuropathy, i.e., Guillain-Barré syndrome) have been reported. Muscular weakness may or may not
occur with the peripheral neuropathies. Visual and psychic disturbances; mental disorders; and agitation and
anxiety have been reported.
Neuromuscular — Myasthenia gravis (see WARNINGS); dystonia.
Other — Adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see
PRECAUTIONS); falling hair or alopecia; lichen planus; polymyositis; dermatomyositis; mammary hyperplasia;
elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and
Goodpasture's syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar
hemorrhage (see WARNINGS). Vasculitis, including fatal renal vasculitis, has also been reported. Allergic
alveolitis, obliterative bronchiolitis, interstitial pneumonitis and pulmonary fibrosis have been reported in patients
with severe rheumatoid arthritis, some of whom were receiving penicillamine. Bronchial asthma also has been
reported.
Increased skin friability, excessive wrinkling of skin, and development of small white papules at venipuncture
and surgical sites have been reported (see PRECAUTIONS); yellow nail syndrome.
The chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury
and lead.
There have been reports associating penicillamine with leukemia. However, circumstances involved in these
reports are such that a cause and effect relationship to the drug has not been established.
DOSAGE AND ADMINISTRATION
In all patients receiving penicillamine, it is important that CUPRIMINE be given on an empty stomach, at
least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food, or
milk. Because penicillamine increases the requirement for pyridoxine, patients may require a daily supplement
of pyridoxine (see PRECAUTIONS).
Wilson's Disease — Optimal dosage can be determined by measurement of urinary copper excretion and
the determination of free copper in the serum. The urine must be collected in copper-free glassware, and should
be quantitatively analyzed for copper before and soon after initiation of therapy with CUPRIMINE.
Determination of 24-hour urinary copper excretion is of greatest value in the first week of therapy with
penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial
24-hour cupriuresis of over 2 mg should be continued for about three months, by which time the most reliable
method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the
difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated
patients will usually have less than 10 mcg free copper/dL of serum. It is seldom necessary to exceed a dosage
of 2 g/day. If the patient is intolerant to therapy with CUPRIMINE, alternative treatment is trientine hydrochloride.
In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and
increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to
reduce the incidence of adverse reactions.
Cystinuria — It is recommended that CUPRIMINE be used along with conventional therapy. By reducing
urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to
decrease the size of, and even to dissolve, stones already formed.
The usual dosage of CUPRIMINE in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to
4 g/day. For pediatric patients, dosage can be based on 30 mg/kg/day. The total daily amount should be divided
into four doses. If four equal doses are not feasible, give the larger portion at bedtime. If adverse reactions
necessitate a reduction in dosage, it is important to retain the bedtime dose.
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Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of
the effects of the drug and may help to reduce the incidence of adverse reactions.
In addition to taking CUPRIMINE, patients should drink copiously. It is especially important to drink about a
pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid
than during the day. The greater the fluid intake, the lower the required dosage of CUPRIMINE.
Dosage must be individualized to an amount that limits cystine excretion to 100-200 mg/day in those with no
history of stones, and below 100 mg/day in those who have had stone formation and/or pain. Thus, in
determining dosage, the inherent tubular defect, the patient's size, age, and rate of growth, and his diet and
water intake all must be taken into consideration.
The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective
dose:† Add 2 mL of freshly prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine
and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. Cystine will
turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than
100 mg/g creatinine.
Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta. If there is any
question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt:
Add 3 percent ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly
fading blue. Cystine will not produce any change in appearance.
Rheumatoid Arthritis — The principal rule of treatment with CUPRIMINE in rheumatoid arthritis is patience.
The onset of therapeutic response is typically delayed. Two or three months may be required before the first
evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).
When treatment with CUPRIMINE has been interrupted because of adverse reactions or other reasons, the
drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.
Initial Therapy — The currently recommended dosage regimen in rheumatoid arthritis begins with a single
daily dose of 125 mg or 250 mg, which is thereafter increased at one to three month intervals, by 125 mg or
250 mg/day, as patient response and tolerance indicate. If a satisfactory remission of symptoms is achieved, the
dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement
and there are no signs of potentially serious toxicity after two to three months of treatment with doses of
500-750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory
remission occurs (see Maintenance Therapy) or signs of toxicity develop (see WARNINGS and
PRECAUTIONS). If there is no discernible improvement after three to four months of treatment with 1000 to
1500 mg of penicillamine/day, it may be assumed the patient will not respond and CUPRIMINE should be
discontinued.
Maintenance Therapy — The maintenance dosage of CUPRIMINE must be individualized, and may require
adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the
500-750 mg/day range. Some need less.
Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation
rate for two to three months after each dosage adjustment.
Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease
suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after
the first six to nine months of treatment, the daily dosage of CUPRIMINE may be increased by 125 mg or
250 mg/day at three-month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day,
but up to 1.5 g/day has sometimes been required.
Management of Exacerbations — During the course of treatment some patients may experience an
exacerbation of disease activity following an initial good response. These may be self-limited and can subside
within twelve weeks. They are usually controlled by the addition of non-steroidal anti-inflammatory drugs, and
only if the patient has demonstrated a true "escape" phenomenon (as evidenced by failure of the flare to
subside within this time period) should an increase in the maintenance dose ordinarily be considered.
In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate
from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in dosage of
CUPRIMINE for up to several weeks will usually determine which of these processes is responsible for the
arthralgia.
† Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J. 2: 521, Aug. 28, 1965 (in Medical Memoranda).
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Duration of Therapy — The optimum duration of therapy with CUPRIMINE in rheumatoid arthritis has not
been determined. If the patient has been in remission for six months or more, a gradual, stepwise dosage
reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted.
Concomitant Drug Therapy — CUPRIMINE should not be used in patients who are receiving gold therapy,
antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see PRECAUTIONS). Other measures,
such as salicylates, other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued
when penicillamine is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be
slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of
treatment with CUPRIMINE may be required before steroids can be completely eliminated.
Dosage Frequency — Based on clinical experience, dosages up to 500 mg/day can be given as a single
daily dose. Dosages in excess of 500 mg/day should be administered in divided doses.
HOW SUPPLIED
No. 3299 — Capsules CUPRIMINE, 250 mg, are ivory-colored capsules containing a white or nearly white
powder, and are coded CUPRIMINE and MSD 602. They are supplied as follows:
NDC 0006-0602-68 in bottles of 100.
No. 3350 — Capsules CUPRIMINE, 125 mg, are opaque ivory and gray capsules containing a white or
nearly white powder, and are coded CUPRIMINE and MSD 672. They are supplied as follows:
NDC 0006-0672-68 in bottles of 100.
Storage
Keep container tightly closed.
Issued Printed in USA
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19853s012,014lbl.pdf', 'application_number': 19853, 'submission_type': 'SUPPL ', 'submission_number': 12}
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CAPSULES
CUPRIMINE®
(PENICILLAMINE)
Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special
dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient
should remain constantly under the close supervision of the physician. Patients should be warned to report
promptly any symptoms suggesting toxicity.
DESCRIPTION
Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine
excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional
therapy (see INDICATIONS). It is 3-mercapto-D-valine. It is a white or practically white, crystalline powder,
freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon
tetrachloride. Although its configuration is D, it is levorotatory as usually measured:
[α] 25°
= -62.5° ± 2° (c = 1, 1N NaOH),
D
calculated on a dried basis.
The empirical formula is C5H11NO2S, giving it a molecular weight of 149.21. The structural formula is:
It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid.
Capsules CUPRIMINE* (Penicillamine) for oral administration contain either 125 mg or 250 mg of
penicillamine. Each capsule contains the following inactive ingredients: D & C Yellow 10, gelatin, lactose,
magnesium stearate, and titanium dioxide. The 125 mg capsule also contains iron oxide.
CLINICAL PHARMACOLOGY
Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's
disease. From in vitro studies which indicate that one atom of copper combines with two molecules of
penicillamine, it would appear that one gram of penicillamine should be followed by the excretion of about 200
milligrams of copper; however, the actual amount excreted is about one percent of this.
Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide
interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a
substance that is much more soluble than cystine and is excreted readily.
Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them
when newly formed.
The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress
disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but
produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic
immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.
In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity
to its effect in rheumatoid arthritis is not known.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1985, 1989,1992
All rights reserved
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In rheumatoid arthritis, the onset of therapeutic response to CUPRIMINE may not be seen for two or three
months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain,
tenderness, and swelling is generally apparent within three months. The optimum duration of therapy has not
been determined. If remissions occur, they may last from months to years, but usually require continued
treatment (see DOSAGE AND ADMINISTRATION).
In all patients receiving penicillamine, it is important that CUPRIMINE be given on an empty stomach, at
least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food,
milk, antacid, zinc or iron-containing preparation. This permits maximum absorption and reduces the likelihood
of inactivation by metal binding in the gastrointestinal tract.
Pharmacokinetics
Penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide inter-
individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of
penicillamine occurs 1-3 hours after ingestion; it is approximately 1-2 mg/L after an oral dose of 250 mg. The
drug appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide.
When prolonged treatment is stopped, there is a slow elimination phase lasting 4-6 days.
More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug
also binds to erythrocytes and macrophages. A small fraction of the dose is metabolized in the liver to S-methyl-
D-penicillamine. Excretion is mainly renal, mainly as disulfides.
INDICATIONS
CUPRIMINE is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active
rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence
suggests that CUPRIMINE is not of value in ankylosing spondylitis.
Wilson’s Disease — Wilson’s disease (hepatolenticular degeneration) occurs in individuals who have
inherited an autosomal recessive defect that leads to an accumulation of copper far in excess of metabolic
requirements. The excess copper is deposited in several organs and tissues, and eventually produces
pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain,
where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown
Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are
either asymptomatic or manifest only hepatic symptomatology.
Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic
in whom it can be assumed the disease will develop in the future if the patient is not treated.
The diagnosis, if suspected on the basis of family or individual history or physical examination, can be
confirmed if the plasma copper-protein ceruloplasmin** is <20 mg/dL and either a quantitative determination in a
liver biopsy specimen shows an abnormally high concentration of copper (>250 mcg/g dry weight) or Kayser-
Fleischer rings are present.
Treatment has two objectives:
(1) to minimize dietary intake of copper;
(2) to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.
The first objective is attained by a daily diet that contains no more than one or two milligrams of copper. Such
a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and
cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of
foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water
contains more than 0.1 mg of copper per liter.
For the second objective, a copper chelating agent is used.
In symptomatic patients this treatment usually produces marked neurologic improvement, fading of Kayser-
Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.
Clinical experience to date suggests that life is prolonged with the above regimen.
Noticeable improvement may not occur for one to three months. Occasionally, neurologic symptoms become
worse during initiation of therapy with CUPRIMINE. Despite this, the drug should not be withdrawn. Temporary
** For quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I.; Scheinberg, I.H.: Measurement of the concentration of
ceruloplasmin in serum by determination of its oxidase activity, in “Laboratory Diagnosis of Liver Disease”, F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St.
Louis, Warren H. Green, Inc., 1968, pp. 193-195.
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interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it
may result in clinical improvement of neurological symptoms (see WARNINGS). If the neurological symptoms
and signs continue to worsen for a month after the initiation of CUPRIMINE therapy, several short courses of
treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE may be considered.
Treatment of asymptomatic patients has been carried out for over thirty years. Symptoms and signs of the
disease appear to be prevented indefinitely if daily treatment with CUPRIMINE is continued.
Cystinuria — Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine,
lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that
leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is
influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular
dysfunction.
Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent
pathology connected with their excretion in excessive quantities.
Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so
crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria.
Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed
1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is
indicated.
Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation,
keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by
a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine
specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in
methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy
because of its low protein content (see PRECAUTIONS).
When these measures are inadequate to control recurrent stone formation, CUPRIMINE may be used as
additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE may be a useful
substitute. It is capable of keeping cystine excretion to near normal values, thereby hindering stone formation
and the serious consequences of pyelonephritis and impaired renal function that develop in some patients.
Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-
cysteine mixed disulfide as:
CSSC + PS′
CS′ + CSSP
PSSP + CS′
PS′ + CSSP
CSSC + PSSP′
2CSSP
CSSC = cystine
CS′ = deprotonated cysteine
PSSP = penicillamine disulfide
PS′ = deprotonated penicillamine sulfhydryl
CSSP = penicillamine-cysteine mixed disulfide
In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing
about the disulfide interchange.
Rheumatoid Arthritis — Because CUPRIMINE can cause severe adverse reactions, its use in rheumatoid
arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an
adequate trial of conventional therapy. Even then, benefit-to-risk ratio should be carefully considered. Other
measures, such as rest, physiotherapy, salicylates, and corticosteroids should be used, when indicated, in
conjunction with CUPRIMINE (see PRECAUTIONS).
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4
CONTRAINDICATIONS
Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during
pregnancy is contraindicated (see WARNINGS).
Although breast milk studies have not been reported in animals or humans, mothers on therapy with
penicillamine should not nurse their infants.
Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on
penicillamine (see WARNINGS and ADVERSE REACTIONS).
Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid
arthritis patients with a history or other evidence of renal insufficiency.
WARNINGS
The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia,
agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.
Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine
urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be
done twice weekly, together with monitoring of the patient's skin, lymph nodes and body temperature, during the
first month of therapy, every two weeks for the next five months, and monthly thereafter. Patients should be
instructed to report promptly the development of signs and symptoms of granulocytopenia and/or
thrombocytopenia such as fever, sore throat, chills, bruising or bleeding. The above laboratory studies should
then be promptly repeated.
Leukopenia and thrombocytopenia have been reported to occur in up to five percent of patients during
penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an
increase in eosinophils. A confirmed reduction in WBC below 3500/mm3 mandates discontinuance of
penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent
megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is
presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be
normal or sometimes increased. The development of a platelet count below 100,000/mm3, even in the absence
of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either
platelet count or WBC in three successive determinations, even though values are still within the normal range,
likewise requires at least temporary cessation.
Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous
glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In
some patients the proteinuria disappears with continued therapy; in others, penicillamine must be discontinued.
When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-
induced glomerulopathy or is unrelated to penicillamine.
Rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on
penicillamine therapy, provided that quantitative 24-hour urinary protein determinations are obtained at intervals
of one to two weeks. Penicillamine dosage should not be increased under these circumstances. Proteinuria
which exceeds 1 g/24 hours, or proteinuria which is progressively increasing, requires either discontinuance of
the drug or a reduction in the dosage. In some patients, proteinuria has been reported to clear following
reduction in dosage.
In rheumatoid arthritis patients penicillamine should be discontinued if unexplained gross hematuria or
persistent microscopic hematuria develops.
In patients with Wilson's disease or cystinuria the risks of continued penicillamine therapy in patients
manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits.
When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. Cystine stones form
rapidly, sometimes in six months.
Up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has
been discontinued.
Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended
every six months for the duration of therapy. In Wilson’s disease, these are recommended every three months,
at least during the first year of treatment.
Goodpasture's syndrome has occurred rarely. The development of abnormal urinary findings associated with
hemoptysis and pulmonary infiltrates on x-ray requires immediate cessation of penicillamine.
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CUPRIMINE® (Penicillamine)
78732XX
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Obliterative bronchiolitis has been reported rarely. The patient should be cautioned to report immediately
pulmonary symptoms such as exertional dyspnea, unexplained cough or wheezing. Pulmonary function studies
should be considered at that time.
Onset of new neurological symptoms has been reported with CUPRIMINE (see ADVERSE REACTIONS).
Occasionally, neurological symptoms become worse during initiation of therapy with CUPRIMINE (see
INDICATIONS). Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis
and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of
cases, symptoms of myasthenia have receded after withdrawal of penicillamine.
Most of the various forms of pemphigus have occurred during treatment with penicillamine. Pemphigus
vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. The
seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. When pemphigus is
suspected, CUPRIMINE should be discontinued. Treatment has consisted of high doses of corticosteroids alone
or, in some cases, concomitantly with an immunosuppressant. Treatment may be required for only a few weeks
or months, but may need to be continued for more than a year.
Once instituted for Wilson's disease or cystinuria, treatment with penicillamine should, as a rule, be
continued on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after
reinstitution of therapy.
Pregnancy Category D
Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine has been shown
to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human
use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.
There are no controlled studies on the use of penicillamine in pregnant women. Although normal outcomes
have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in
infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should be used
in women of childbearing potential only when the expected benefits outweigh the possible hazards. Women on
therapy with penicillamine who are of childbearing potential should be apprised of this risk, advised to report
promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early
recognition of pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard to the fetus.
Wilson's Disease — Reported experience*** shows that continued treatment with penicillamine throughout
pregnancy protects the mother against relapse of the Wilson's disease, and that discontinuation of penicillamine
has deleterious effects on the mother, which may be fatal.
If penicillamine is administered during pregnancy to patients with Wilson's disease, it is recommended that
the daily dosage be limited to 750 mg. If cesarean section is planned the daily dose should be reduced to
250 mg, but not lower, for the last six weeks of pregnancy and postoperatively until wound healing is complete.
Cystinuria — If possible, penicillamine should not be given during pregnancy to women with cystinuria (see
CONTRAINDICATIONS). There are reports of women with cystinuria on therapy with penicillamine who gave
birth to infants with generalized connective tissue defects who died following abdominal surgery. If stones
continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the
fetus.
Rheumatoid Arthritis — Penicillamine should not be administered to rheumatoid arthritis patients who are
pregnant (see CONTRAINDICATIONS) and should be discontinued promptly in patients in whom pregnancy is
suspected or diagnosed.
There is a report that a woman with rheumatoid arthritis treated with less than one gram a day of
penicillamine during pregnancy gave birth (cesarean delivery) to an infant with growth retardation, flattened face
with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin.
PRECAUTIONS
Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second
to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous
eruption.
In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily
discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is
*** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med. 293: 1300-1302, Dec. 18, 1975.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
78732XX
XXXXXXX
6
gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is
usually helpful, in such patients in whom drug fever and rash develop several times.
In the case of drug fever in rheumatoid arthritis patients, because other treatments are available,
penicillamine should be discontinued and another therapeutic alternative tried since experience indicates that
the febrile reaction will recur in a very high percentage of patients upon readministration of penicillamine.
The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have
occurred. Early rash occurs during the first few months of treatment and is more common. It is usually a
generalized pruritic, erythematous, maculopapular or morbilliform rash and resembles the allergic rash seen
with other drugs. Early rash usually disappears within days after stopping penicillamine and seldom recurs when
the drug is restarted at a lower dosage. Pruritus and early rash may often be controlled by the concomitant
administration of antihistamines. Less commonly, a late rash may be seen, usually after six months or more of
treatment, and requires discontinuation of penicillamine. It is usually on the trunk, is accompanied by intense
pruritus, and is usually unresponsive to topical corticosteroid therapy. Late rash may take weeks to disappear
after penicillamine is stopped and usually recurs if the drug is restarted.
The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic
manifestations usually requires discontinuation of penicillamine.
Certain patients will develop a positive antinuclear antibody (ANA) test and some of these may show a lupus
erythematosus-like syndrome similar to drug-induced lupus associated with other drugs. The lupus
erythematosus-like syndrome is not associated with hypocomplementemia and may be present without
nephropathy. The development of a positive ANA test does not mandate discontinuance of the drug; however,
the physician should be alerted to the possibility that a lupus erythematosus-like syndrome may develop in the
future.
Some patients may develop oral ulcerations which in some cases have the appearance of aphthous
stomatitis. The stomatitis usually recurs on rechallenge but often clears on a lower dosage. Although rare,
cheilosis, glossitis and gingivostomatitis have also been reported. These oral lesions are frequently dose-related
and may preclude further increase in penicillamine dosage or require discontinuation of the drug.
Hypogeusia (a blunting or diminution in taste perception) has occurred in some patients. This may last two to
three months or more and may develop into a total loss of taste; however, it is usually self-limited despite
continued penicillamine treatment. Such taste impairment is rare in patients with Wilson's disease.
Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or
cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar
serious hematologic and renal adverse reactions. Patients who have had gold salt therapy discontinued due to a
major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of
the same type.
Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine. The possibility
of reactions from contamination of penicillamine by trace amounts of penicillin has been eliminated now that
penicillamine is being produced synthetically rather than as a degradation product of penicillin.
Patients with Wilson’s disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since
penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin
preparation, although there is no evidence that deficiency of any vitamin other than pyridoxine is associated with
penicillamine. In Wilson's disease, multivitamin preparations must be copper-free.
Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of
pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
Iron deficiency may develop, especially in pediatric patients and in menstruating women. In Wilson's disease,
this may be a result of adding the effects of the low copper diet, which is probably also low in iron, and the
penicillamine to the effects of blood loss or growth. In cystinuria, a low methionine diet may contribute to iron
deficiency, since it is necessarily low in protein. If necessary, iron may be given in short courses, but a period of
two hours should elapse between administration of penicillamine and iron, since orally administered iron has
been shown to reduce the effects of penicillamine.
Penicillamine causes an increase in the amount of soluble collagen. In the rat this results in inhibition of
normal healing and also a decrease in tensile strength of intact skin. In man this may be the cause of increased
skin friability at sites especially subject to pressure or trauma, such as shoulders, elbows, knees, toes, and
buttocks. Extravasations of blood may occur and may appear as purpuric areas, with external bleeding if the
skin is broken, or as vesicles containing dark blood. Neither type is progressive. There is no apparent
association with bleeding elsewhere in the body and no associated coagulation defect has been found. Therapy
with penicillamine may be continued in the presence of these lesions. They may not recur if dosage is reduced.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
78732XX
XXXXXXX
7
Other reported effects probably due to the action of penicillamine on collagen are excessive wrinkling of the skin
and development of small, white papules at venipuncture and surgical sites.
The effects of penicillamine on collagen and elastin make it advisable to consider a reduction in dosage to
250 mg/day, when surgery is contemplated. Reinstitution of full therapy should be delayed until wound healing is
complete.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that five of
ten autoimmune disease-prone NZB hybrid mice developed lymphocytic leukemia after 6 months' intraperitoneal
treatment with a dose of 400 mg/kg penicillamine 5 days per week.
Penicillamine is directly mutagenic to S. typhimurium strain TA92 in the Ames test; mutagenicity is enhanced
by kidney postmitochondrial subcellular fraction 9. Penicillamine does not induce gene mutations in Chinese
hamster V79 cells.
Penicillamine induces sister-chromatid exchanges and chromosome aberrations in cultivated mammalian
cells.No studies on the effect of penicillamine on fertility are available.
Pregnancy
Pregnancy Category D
(see WARNINGS, Pregnancy)
Nursing Mothers
See CONTRAINDICATIONS.
Pediatric Use
The efficacy of CUPRIMINE in juvenile rheumatoid arthritis has not been established.
Geriatric Use
Clinical studies of CUPRIMINE are limited in subjects aged 65 and over, they did not include sufficient
numbers of elderly subjects aged 65 and over to adequately determine whether they respond differently from
younger subjects. Review of reported clinical trials with penicillamine in the elderly suggest greater risk than in
younger patients for overall skin rash and abnormality of taste. In general, dose selection for an elderly patient
should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal or cardiac function, and of concomitant disease or other drugs.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may
be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and careful monitoring of renal function is recommended.
ADVERSE REACTIONS
Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervision
throughout the period of drug administration (see WARNINGS and PRECAUTIONS).
Reported incidences (%) for the most commonly occurring adverse reactions in rheumatoid arthritis patients
are noted, based on 17 representative clinical trials reported in the literature (1270 patients).
Allergic — Generalized pruritus, early and late rashes (5%), pemphigus (see WARNINGS), and drug
eruptions which may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see WARNINGS
and PRECAUTIONS). Some patients may show a lupus erythematosus-like syndrome similar to drug-induced
lupus produced by other pharmacological agents (see PRECAUTIONS).
Urticaria and exfoliative dermatitis have occurred.
Thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported.
These reactions are extremely rare.
Some patients may develop a migratory polyarthralgia, often with objective synovitis (see DOSAGE AND
ADMINISTRATION).
Gastrointestinal — Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%).
Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction including hepatic
failure, and pancreatitis. Intrahepatic cholestasis and toxic hepatitis have been reported rarely. There have been
a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation
and thymol turbidity tests.
Some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral
ulcerations. Although rare, cheilosis, glossitis, and gingivostomatitis have been reported (see PRECAUTIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
78732XX
XXXXXXX
8
Gastrointestinal side effects are usually reversible following cessation of therapy.
Hematological — Penicillamine can cause bone marrow depression (see WARNINGS). Leukopenia (2%)
and thrombocytopenia (4%) have occurred. Fatalities have been reported as a result of thrombocytopenia,
agranulocytosis, aplastic anemia, and sideroblastic anemia.
Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis,
eosinophilia, and thrombocytosis have also been reported.
Renal — Patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some,
may progress to the development of the nephrotic syndrome as a result of an immune complex membranous
glomerulopathy (see WARNINGS). Renal failure has been reported.
Central Nervous System — Tinnitus, optic neuritis and peripheral sensory and motor neuropathies (including
polyradiculoneuropathy, i.e., Guillain-Barré syndrome) have been reported. Muscular weakness may or may not
occur with the peripheral neuropathies. Visual and psychic disturbances; mental disorders; and agitation and
anxiety have been reported.
Neuromuscular — Myasthenia gravis (see WARNINGS); dystonia.
Other — Adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see
PRECAUTIONS); falling hair or alopecia; lichen planus; polymyositis; dermatomyositis; mammary hyperplasia;
elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and
Goodpasture's syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar
hemorrhage (see WARNINGS). Vasculitis, including fatal renal vasculitis, has also been reported. Allergic
alveolitis, obliterative bronchiolitis, interstitial pneumonitis and pulmonary fibrosis have been reported in patients
with severe rheumatoid arthritis, some of whom were receiving penicillamine. Bronchial asthma also has been
reported.
Increased skin friability, excessive wrinkling of skin, and development of small white papules at venipuncture
and surgical sites have been reported (see PRECAUTIONS); yellow nail syndrome.
The chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury
and lead.
There have been reports associating penicillamine with leukemia. However, circumstances involved in these
reports are such that a cause and effect relationship to the drug has not been established.
DOSAGE AND ADMINISTRATION
In all patients receiving penicillamine, it is important that CUPRIMINE be given on an empty stomach, at
least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food, or
milk. Because penicillamine increases the requirement for pyridoxine, patients may require a daily supplement
of pyridoxine (see PRECAUTIONS).
Wilson's Disease — Optimal dosage can be determined by measurement of urinary copper excretion and
the determination of free copper in the serum. The urine must be collected in copper-free glassware, and should
be quantitatively analyzed for copper before and soon after initiation of therapy with CUPRIMINE.
Determination of 24-hour urinary copper excretion is of greatest value in the first week of therapy with
penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial
24-hour cupriuresis of over 2 mg should be continued for about three months, by which time the most reliable
method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the
difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated
patients will usually have less than 10 mcg free copper/dL of serum. It is seldom necessary to exceed a dosage
of 2 g/day. If the patient is intolerant to therapy with CUPRIMINE, alternative treatment is trientine hydrochloride.
In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and
increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to
reduce the incidence of adverse reactions.
Cystinuria — It is recommended that CUPRIMINE be used along with conventional therapy. By reducing
urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to
decrease the size of, and even to dissolve, stones already formed.
The usual dosage of CUPRIMINE in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to
4 g/day. For pediatric patients, dosage can be based on 30 mg/kg/day. The total daily amount should be divided
into four doses. If four equal doses are not feasible, give the larger portion at bedtime. If adverse reactions
necessitate a reduction in dosage, it is important to retain the bedtime dose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
78732XX
XXXXXXX
9
Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of
the effects of the drug and may help to reduce the incidence of adverse reactions.
In addition to taking CUPRIMINE, patients should drink copiously. It is especially important to drink about a
pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid
than during the day. The greater the fluid intake, the lower the required dosage of CUPRIMINE.
Dosage must be individualized to an amount that limits cystine excretion to 100-200 mg/day in those with no
history of stones, and below 100 mg/day in those who have had stone formation and/or pain. Thus, in
determining dosage, the inherent tubular defect, the patient's size, age, and rate of growth, and his diet and
water intake all must be taken into consideration.
The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective
dose:† Add 2 mL of freshly prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine
and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. Cystine will
turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than
100 mg/g creatinine.
Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta. If there is any
question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt:
Add 3 percent ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly
fading blue. Cystine will not produce any change in appearance.
Rheumatoid Arthritis — The principal rule of treatment with CUPRIMINE in rheumatoid arthritis is patience.
The onset of therapeutic response is typically delayed. Two or three months may be required before the first
evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).
When treatment with CUPRIMINE has been interrupted because of adverse reactions or other reasons, the
drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.
Initial Therapy — The currently recommended dosage regimen in rheumatoid arthritis begins with a single
daily dose of 125 mg or 250 mg, which is thereafter increased at one to three month intervals, by 125 mg or
250 mg/day, as patient response and tolerance indicate. If a satisfactory remission of symptoms is achieved, the
dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement
and there are no signs of potentially serious toxicity after two to three months of treatment with doses of
500-750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory
remission occurs (see Maintenance Therapy) or signs of toxicity develop (see WARNINGS and
PRECAUTIONS). If there is no discernible improvement after three to four months of treatment with 1000 to
1500 mg of penicillamine/day, it may be assumed the patient will not respond and CUPRIMINE should be
discontinued.
Maintenance Therapy — The maintenance dosage of CUPRIMINE must be individualized, and may require
adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the
500-750 mg/day range. Some need less.
Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation
rate for two to three months after each dosage adjustment.
Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease
suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after
the first six to nine months of treatment, the daily dosage of CUPRIMINE may be increased by 125 mg or
250 mg/day at three-month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day,
but up to 1.5 g/day has sometimes been required.
Management of Exacerbations — During the course of treatment some patients may experience an
exacerbation of disease activity following an initial good response. These may be self-limited and can subside
within twelve weeks. They are usually controlled by the addition of non-steroidal anti-inflammatory drugs, and
only if the patient has demonstrated a true "escape" phenomenon (as evidenced by failure of the flare to
subside within this time period) should an increase in the maintenance dose ordinarily be considered.
In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate
from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in dosage of
CUPRIMINE for up to several weeks will usually determine which of these processes is responsible for the
arthralgia.
† Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J. 2: 521, Aug. 28, 1965 (in Medical Memoranda).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CUPRIMINE® (Penicillamine)
78732XX
XXXXXXX
10
Duration of Therapy — The optimum duration of therapy with CUPRIMINE in rheumatoid arthritis has not
been determined. If the patient has been in remission for six months or more, a gradual, stepwise dosage
reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted.
Concomitant Drug Therapy — CUPRIMINE should not be used in patients who are receiving gold therapy,
antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see PRECAUTIONS). Other measures,
such as salicylates, other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued
when penicillamine is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be
slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of
treatment with CUPRIMINE may be required before steroids can be completely eliminated.
Dosage Frequency — Based on clinical experience, dosages up to 500 mg/day can be given as a single
daily dose. Dosages in excess of 500 mg/day should be administered in divided doses.
HOW SUPPLIED
No. 3299 — Capsules CUPRIMINE, 250 mg, are ivory-colored capsules containing a white or nearly white
powder, and are coded CUPRIMINE and MSD 602. They are supplied as follows:
NDC 0006-0602-68 in bottles of 100.
No. 3350 — Capsules CUPRIMINE, 125 mg, are opaque ivory and gray capsules containing a white or
nearly white powder, and are coded CUPRIMINE and MSD 672. They are supplied as follows:
NDC 0006-0672-68 in bottles of 100.
Storage
Keep container tightly closed.
Issued Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19853s012,014lbl.pdf', 'application_number': 19853, 'submission_type': 'SUPPL ', 'submission_number': 14}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CIPRO
IV® safely and effectively. See full prescribing information for CIPRO IV.
CIPRO IV (ciprofloxacin) injection, for intravenous use
Initial U.S. Approval: 1990
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
See full prescribing information for complete boxed warning.
•
Fluoroquinolones, including CIPRO IV®, are associated with an
increased risk of tendinitis and tendon rupture in all ages. This
risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants. (5.1)
•
Fluoroquinolones, including CIPRO IV, may exacerbate muscle
weakness in persons with myasthenia gravis. Avoid CIPRO IV in
patients with known history of myasthenia gravis. (5.2)
-------------------------- RECENT MAJOR CHANGES -------------------------
Indications and Usage, Plague (1.12)
2/2015
Dosage and Administration, Adults (2.1), Pediatrics (2.2)
2/2015
--------------------------- INDICATIONS AND USAGE -------------------------
CIPRO IV is a fluoroquinolone antibacterial indicated in adults (≥18 years of
age) with infections caused by designated, susceptible bacteria and in
pediatric patients where indicated.
•
Urinary tract infections in adults (1.1)
•
Lower respiratory tract infections in adults (1.2)
•
Nosocomial Pneumonia (1.3)
•
Skin and skin structure infections in adults (1.4)
•
Bone and joint infections in adults (1.5)
•
Complicated intra-abdominal infections in adults (1.6)
•
Acute sinusitis in adults (1.7)
•
Chronic bacterial prostatitis in adults (1.8)
•
Empirical therapy for febrile neutropenic patients (1.9)
•
Complicated urinary tract infections and pyelonephritis in pediatric
patients (1.10)
•
Inhalational anthrax postexposure in adult and pediatric patients (1.11)
•
Plague in adult and pediatric patients (1.12)
•
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV
should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria. (1.14)
---------------------- DOSAGE AND ADMINISTRATION ---------------------
Adult Dosage Guidelines
Infection
Dose
Frequency
Duration
Urinary Tract
200 to 400 mg
every 12 to 8 hours
7–14 days
Lower Respiratory Tract
400 mg
every 12 to 8 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Skin and Skin Structure
400 mg
every 12 to 8 hours
7–14 days
Bone and Joint
400 mg
every 12 to 8 hours 4 to 8 weeks
Intra-Abdominal
400 mg
every 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
Chronic Bacterial
prostatitis
400 mg
every 12 hours
28 days
Empirical Therapy In
Febrile Neutropenic
Patients
400 mg
and
every 8 hours
Piperacillin
50 mg/kg
every 4 hours
7–14 days
Inhalational
anthrax(post-exposure)
400 mg
every 12 hours
60 days
Plague
400 mg
every 12 to 8 hours
14 days
•
Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h
Pediatric Intravenous Dosing Guidelines
Infection
Dose
Frequency
Duration
Complicated Urinary
Tract or Pyelonephritis
(patients from 1 to 17
years of age)
6 mg/kg to 10 mg/kg
(maximum 400 mg
per dose)
Every 8
hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)
10 mg/kg
(maximum 400 mg
per dose)
Every 12
hours
60 days
Plague
10 mg/kg
(maximum 400 mg
per dose)
Every 12
to 8 hours
10–21 days
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
•
Injection: 400 mg/200 mL
------------------------------ CONTRAINDICATIONS ----------------------------
•
Known sensitivity to CIPRO or other quinolones (4.1, 5.3)
•
Concomitant administration with tizanidine (4.2)
----------------------- WARNINGS AND PRECAUTIONS ---------------------
•
Hypersensitivity and other serious reactions: Serious and sometimes
fatal reactions may occur after first or subsequent doses. Discontinue at
first sign of skin rash, jaundice or any sign of hypersensitivity. (4.1, 5.3,
5.4)
•
Hepatotoxicity: Discontinue immediately if signs and symptoms of
hepatitis occur. (5.5)
•
Central nervous system effects, including convulsions, increased
intracranial pressure (pseudotumor cerebri) and toxic psychosis have
been reported. Caution should be taken in patients predisposed to
seizures. (5.7)
•
Clostridium difficile-associated diarrhea: Evaluate if colitis occurs. (5.8)
•
Peripheral neuropathy: Discontinue if symptoms occur in order to
prevent irreversibility. (5.9)
•
QT Prolongation: Prolongation of the QT interval and isolated cases of
torsade de pointes have been reported. Avoid use in patients with known
prolongation, those with hypokalemia, and with other drugs that prolong
the QT interval. (5.10, 7, 8.5)
------------------------------ ADVERSE REACTIONS ----------------------------
The most common adverse reactions ≥1% were nausea, diarrhea, liver
function tests abnormal, vomiting, central nervous system disturbance, local
intravenous site reactions eosinophilia, headache, restlessness, and rash. (6)
TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT
BAYER HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1
800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS ----------------------------
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant
use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor
prothrombin time, INR, and bleeding 7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have
been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum
creatinine (7)
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
See full prescribing information for pediatric patients (8.4) and use in
geriatric (8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS
Reference ID: 3718341
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNING: TENDON EFFECTS AND MYASTHENIA GRAVIS
1 INDICATIONS AND USAGE
1.1 Urinary Tract Infections
1.2 Lower Respiratory Tract Infections
1.3 Nosocomial Pneumonia
1.4 Skin and Skin Structure Infections
1.5 Bone and Joint Infections
1.6 Complicated Intra-Abdominal Infections
1.7 Acute Sinusitis
1.8 Chronic Bacterial Prostatitis
1.9 Empirical Therapy for Febrile Neutropenic Patients
1.10 Complicated Urinary Tract Infections and Pyelonephritis
1.11 Inhalational Anthrax (post-exposure)
1.12 Plague
1.13 Limitations of Use
1.14 Usage
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in Adults
2.2 Dosage in Pediatric Patients
2.3 Preparation of CIPRO IV for Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Hypersensitivity
4.2 Tizanidine
5 WARNINGS AND PRECAUTIONS
5.1 Tendinopathy and Tendon Rupture
5.2 Exacerbation of Myasthenia Gravis
5.3 Hypersensitivity Reactions
5.4 Other Serious and Sometimes Fatal Reactions
5.5 Hepatotoxicity
5.6 Serious Adverse Reactions with Concomitant Theophylline
5.7 Central Nervous System Effects
5.8 Clostridium Difficile-Associated Diarrhea
5.9 Peripheral Neuropathy
5.10 Prolongation of the QT Interval
5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic
Effects in Animals
5.12 Crystalluria
5.13 Photosensitivity/Phototoxicity
5.14 Development of Drug Resistant Bacteria
5.15 Potential Risks With Concomitant Use of Drugs Metabolized by
Cytochrome P450 1A2 Enzymes
5.16 Periodic Assessment of Organ System Functions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Adverse Laboratory Changes
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in
Pediatric Patients
14.3 Inhalational Anthrax in Adults and Pediatrics
14.4 Plague
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
STORAGE
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
Fluoroquinolones, including CIPRO IV® , are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants
[see Warnings and Precautions (5.1)].
Fluoroquinolones, including CIPRO IV, may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis [see
Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
CIPRO IV is indicated for the treatment of infections caused by susceptible isolates of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration is needed [see Dosage and Administration (2.1, 2.2)].
1.1 Urinary Tract Infections
CIPRO IV is indicated in adult patients for treatment of urinary tract infections caused by Escherichia
coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
rettgeri, Morganella morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa,
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methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus
faecalis.
1.2 Lower Respiratory Tract Infections
CIPRO IV is indicated in adult patients for treatment of lower respiratory tract infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae.* Also,
CIPRO IV is indicated for the treatment of acute exacerbations of chronic bronchitis caused by Moraxella
catarrhalis [see Indications and Usage (1.13)].
1.3 Nosocomial Pneumonia
CIPRO IV is indicated in adult patients for treatment of nosocomial pneumonia caused by caused by
Haemophilus influenzae or Klebsiella pneumoniae.
1.4 Skin and Skin Structure Infections
CIPRO IV is indicated in adult patients for treatment of skin and skin structure infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin
susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
1.5 Bone and Joint Infections
CIPRO IV is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter
cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
1.6 Complicated Intra-Abdominal Infections
CIPRO IV is indicated in adult patients for treatment of complicated intra-abdominal infections (used in
combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
1.7 Acute Sinusitis
CIPRO IV is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus
influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
1.8 Chronic Bacterial Prostatitis
CIPRO IV is indicated in adult patients for treatment of chronic bacterial prostatitis caused by
Escherichia coli or Proteus mirabilis.
1.9 Empirical Therapy for Febrile Neutropenic Patients
CIPRO IV is indicated in adult patients for the treatment of febrile neutropenia in combination with
piperacillin sodium [see Clinical Studies (14.1)].
1.10 Complicated Urinary Tract Infections and Pyelonephritis
CIPRO IV is indicated in pediatric patients one to 17 years of age for treatment of complicated urinary
tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Indications and Usage (1.13), Use
in Specific Populations (8.4), and Clinical Studies (14.2)].
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1.11 Inhalational Anthrax (post-exposure)
CIPRO IV is indicated in adults and pediatric patients from birth to 17 years of age for treatment of
inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure
to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely
to predict clinical benefit and provided the initial basis for approval of this indication.1 Supportive clinical
information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax
bioterror attacks of October 2001. [See Clinical Studies (14.3).]
1.12 Plague
CIPRO IV is indicated for treatment of plague, including pneumonic and septicemic plague, due to
Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17
years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for
feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see
Clinical Studies (14.4)].
1.13 Limitation of Use
Use in Pediatric Patients
Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population
due to an increased incidence of adverse events compared to controls, including events related to joints
and/or surrounding tissues. CIPRO IV, like other fluoroquinolones, is associated with arthropathy and
histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions
(5.11), Adverse Reactions (6.1), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].
Lower Respiratory Tract Infections
CIPRO IV is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to
Streptococcus pneumoniae [see Indications and Usage (1.2)].
1.14 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and
other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are
available, they should be considered in selecting or modifying antibacterial therapy. In the absence of
such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in order
to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO IV may be initiated before results of these tests are known; once results become
available appropriate therapy should be continued. As with other drugs, some isolates of Pseudomonas
aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and
susceptibility testing performed periodically during therapy will provide information not only on the
therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.
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2 DOSAGE AND ADMINISTRATION
CIPRO IV should be administered intravenously at dosages described in the appropriate Dosage
Guidelines tables.
2.1 Dosage in Adults
The determination of dosage and duration for any particular patient must take into consideration the
severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the
patient’s host-defense mechanisms, and the status of renal and hepatic function.
Table 1: Adult Dosage Guidelines
Infection1
Dose
Frequency
Usual Duration
Urinary Tract
200 mg to 400 mg
every 12 to every 8 hours
7–14 days
Lower Respiratory Tract
400 mg
every 12 to every 8 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Skin and Skin Structure
400 mg
every 12 to every 8 hours
7–14 days
Bone and Joint
400 mg
every 12 to every 8 hours
4 to 8 weeks
Complicated Intra-Abdominal2
400 mg
every 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
Chronic Bacterial prostatitis
400 mg
every 12 hours
28 days
CIPRO IV
Empirical Therapy In Febrile
Neutropenic Patients
400 mg
and
Piperacillin
50 mg/kg
every 8 hours
every 4 hours
7–14 days
Inhalational anthrax(post-exposure)3
400 mg
every 12 hours
60 days
Plague3
400 mg
every 12 to 8 hours
14 days
1.
Due to the designated pathogens (see Indications and Usage.)
2.
Used in conjunction with metronidazole.
3.
Begin administration as soon as possible after suspected or confirmed exposure.
Conversion of Intravenous to Oral Dosing in Adults
Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension
when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology (12.3)].
Table 2: Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO IV Dosage
250 mg Tablet every 12 hours
200 mg intravenous every 12 hours
500 mg Tablet every 12 h
400 mg intravenous every 12 hours
750 mg Tablet every 12 hours
400 mg intravenous every 8 hours
2.2 Dosage in Pediatric Patients
Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by
the severity of the infection.
5
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1.
2.
3.
2.3
Ci
Table 3: Pediatric Dosage Guidelines
Infection
Dose
(mg/kg)
Frequency
Total Duration
Complicated Urinary Tract or
Pyelonephritis
(patients from 1 to 17 years of age)1
6 mg/kg to 10 mg/kg
(maximum 400 mg per dose; not to
be exceeded even in patients
weighing more than 51 kg)
Every 8 hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)2
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
60 days
Plague2,3
10 mg/kg
(maximum 400 mg per dose)
Every 12 to 8
hours
10–21 days
The total duration of therapy for cUTI and pyelonephritis in the clinical trial was determined by the physician. The mean
duration of treatment was 11 days (range 10 to 21 days).
Begin drug administration as soon as possible after suspected or confirmed exposure.
Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis.
Dosage Modifications in Patients with Renal Impairment
profloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table
4.
Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal
Function
Creatinine Clearance (mL/min)
Dose
>30
See Usual Dosage.
5–29
200–400 mg every 18–24 hours
When only the serum creatinine concentration is known, the following formulas may be used to estimate
creatinine clearance:
Men - Creatinine clearance (mL/min) = Weight (kg) x (140 – age)
72 x serum creatinine (mg/dL)
Women - 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment and hepatic insufficiency, careful
monitoring is suggested.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric
patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m2).
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2.3 Preparation of CIPRO IV for Administration
Flexible Containers
CIPRO IV is available as a 0.2% premixed solution in 5% dextrose in flexible containers of 200 mL. The
solutions in flexible containers do not need to be diluted and may be infused as described above.
2.4 Important Administration Instructions
Intravenous Infusion
CIPRO IV should be administered to by intravenous infusion over a period of 60 minutes. Slow infusion
of a dilute solution into a larger vein will minimize patient discomfort and reduce the risk of venous
irritation.
Hydration of Patients Receiving CIPRO IV
Adequate hydration of patients receiving CIPRO IV should be maintained to prevent the formation of
highly concentrated urine. Crystalluria has been reported with quinolones [see Warnings and Precautions
(5.12), Adverse Reactions (6.1), Nonclinical Toxicology (13.2) and Patient Counseling Information (17)].
3 DOSAGE FORMS AND STRENGTHS
Injection (200 mL in 5% Dextrose, 400 mg, 0.2%) Premix in Flexible Containers, for intravenous
infusion
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antibacterials, or any of the product components [see Warnings and
Precautions (5.3)].
4.2 Tizanidine
Concomitant administration with tizanidine is contraindicated [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1 Tendinopathy and Tendon Rupture
Fluoroquinolones, including CIPRO IV, are associated with an increased risk of tendinitis and tendon
rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the
Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the
shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of
developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or
lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the
risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders
such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking
fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can occur,
sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases
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occurring up to several months after completion of therapy have been reported. CIPRO IV should be used
with caution in patients with a history of tendon disorders. CIPRO IV should be discontinued if the
patient experiences pain, swelling, inflammation or rupture of a tendon. [See Adverse Reactions (6.2).]
5.2 Exacerbation of Myasthenia Gravis
Fluoroquinolones, including CIPRO IV, have neuromuscular blocking activity and may exacerbate
muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including
deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons
with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis. [See Adverse
Reactions (6.2).]
5.3 Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose,
have been reported in patients receiving quinolone therapy, including CIPRO IV. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema,
dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious
anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation
measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor
amines, and airway management, including intubation, as indicated. [See Adverse Reactions (6.1)].
5.4 Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported in patients receiving therapy with quinolones, including CIPRO IV. These
events may be severe and generally occur following the administration of multiple doses. Clinical
manifestations may include one or more of the following:
• Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-
Johnson syndrome);
• Vasculitis; arthralgia; myalgia; serum sickness;
• Allergic pneumonitis;
• Interstitial nephritis; acute renal insufficiency or failure;
• Hepatitis; jaundice; acute hepatic necrosis or failure;
• Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
Discontinue CIPRO IV immediately at the first appearance of a skin rash, jaundice, or any other sign of
hypersensitivity and supportive measures instituted [see Adverse Reactions (6.1, 6.2)].
5.5 Hepatotoxicity
Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal
events, have been reported with CIPRO IV. Acute liver injury is rapid in onset (range 1–39 days), and is
often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed.
Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms
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of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment
immediately.
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice,
especially in patients with previous liver damage, who are treated with CIPRO IV. [See Adverse
Reactions (6.2, 6.3).]
5.6 Serious Adverse Reactions with Concomitant Theophylline
Serious and fatal reactions have been reported in patients receiving concurrent administration of
Intravenous CIPRO and theophylline. These reactions have included cardiac arrest, seizure, status
epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have
also occurred.
Although similar serious adverse reactions have been reported in patients receiving theophylline alone,
the possibility that these reactions may be potentiated by CIPRO cannot be eliminated. If concomitant use
cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Drug
Interactions (7).]
5.7 Central Nervous System Effects
Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have
been reported in patients receiving fluoroquinolones, including CIPRO IV. CIPRO IV may also cause
central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares,
paranoia, dizziness, confusion, tremors, hallucinations, depression, and, psychotic reactions have
progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed
suicide. These reactions may occur following the first dose. Advise patients receiving CIPRO IV to
inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute
appropriate care. CIPRO IV, like other fluoroquinolones, is known to trigger seizures or lower the seizure
threshold. As with all fluoroquinolones, use CIPRO with caution in epileptic patients and patients with
known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for
example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow,
altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures
or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). Use CIPRO IV
when the benefits of treatment exceed the risks, since these patients are endangered because of possible
undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur,
discontinue CIPRO. [See Adverse Reactions (6.1) and Drug Interactions (7).]
5.8 Clostridium Difficile-Associated Diarrhea
Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including CIPRO IV, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.
difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients
who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD
has been reported to occur over two months after the administration of antibacterial agents.
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If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial
treatment of C. difficile, and institute surgical evaluation as clinically indicated. [See Adverse Reactions
(6.1).]
5.9 Peripheral Neuropathy
Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in
paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving
fluoroquinolones, including CIPRO IV. Symptoms may occur soon after initiation of CIPRO IV and may
be irreversible. Discontinue CIPRO IV immediately if the patient experiences symptoms of peripheral
neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in
sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor
strength in order to minimize the development of an irreversible condition. [See Adverse Reactions (6.1,
6.2).]
5.10 Prolongation of the QT Interval
Some fluoroquinolones, including CIPRO IV, have been associated with prolongation of the QT interval
on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during
postmarketing surveillance in patients receiving fluoroquinolones, including CIPRO IV. Avoid CIPRO IV
in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de
pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as
hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or
bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class
III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.
Elderly patients may also be more susceptible to drug-associated effects on the QT interval. [See Adverse
Reactions (6.2) and Use in Specific Populations (8.5).]
5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
CIPRO IV is indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of
inhalational anthrax (post exposure), and plague [see Indications and Usage (1.10, 1.11, 1.12)]. An
increased incidence of adverse reactions compared to controls, including reactions related to joints and/or
surrounding tissues, has been observed [see Adverse Reactions (6.1)].
In pre-clinical studies, oral administration of CIPRO IV caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. [See Use in Specific Populations
(8.4) and Nonclinical Toxicology (13.2).]
5.12 Crystalluria
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in
the urine of laboratory animals, which is usually alkaline [see Nonclinical Toxicology (13.2)]. Crystalluria
related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic.
Avoid alkalinity of the urine in patients receiving CIPRO IV. Hydrate patients well to prevent the
formation of highly concentrated urine [see Dosage and Administration (2.4)].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.13 Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as
exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema)
involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the
forearms, dorsa of the hands), can be associated with the use of quinolones, including CIPRO IV, after
sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue
CIPRO IV if phototoxicity occurs. [See Adverse Reactions (6.1).]
5.14 Development of Drug Resistant Bacteria
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
5.15 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2
Enzymes
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of CIPRO IV
and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine,
tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co
administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co
administered drug. [See Drug Interactions (7) and Clinical Pharmacology (12.3).]
5.16 Periodic Assessment of Organ System Functions
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
6 ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail
in other sections of labeling:
• Tendon Effects [see Warnings and Precautions (5.1)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.4)]
• Hepatotoxicity [see Warnings and Precautions (5.5)]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions
(5.6)]
• Central Nervous System Effects [see Warnings and Precautions (5.7)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.8)]
• Peripheral Neuropathy [see Warnings and Precautions (5.9)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.10)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.11)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]
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6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adult Patients
During clinical investigations with oral and parenteral CIPRO IV, 49,038 patients received courses of the
drug.
The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
In clinical trials the following adverse reactions were reported in greater than 1% of patients treated with
intravenous CIPRO IV: nausea, diarrhea, central nervous system disturbance, local intravenous site
reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Local intravenous
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin
reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is
not contraindicated unless the reactions recur or worsen.
Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin
Patients
System Organ Class
Adverse Reactions
Body as a Whole
Abdominal Pain/Discomfort
Pain
Cardiovascular
Cardiopulmonary Arrest
Myocardial Infarction
Tachycardia
Syncope
Hypertension
Angina Pectoris
Vasodilation
Central Nervous System
Restlessness
Seizures (including Status Epilepticus)
Paranoia
Psychosis (toxic)
Depression (potentially culminating in self-injurious behavior,
such as suicidal ideations/thoughts and attempted or completed
suicide)
Phobia
Depersonalization
Manic Reaction
Unresponsiveness
Ataxia
Hallucinations
Dizziness
Paresthesia
Tremor
Insomnia
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System Organ Class
Adverse Reactions
Nightmares
Irritability
Malaise
Abnormal Gait
Migraine
Gastrointestinal
Ileus
Gastrointestinal Bleeding
Pancreatitis
Hepatic Necrosis
Intestinal Perforation
Dyspepsia
Constipation
Oral Ulceration
Mouth Dryness
Anorexia
Flatulence
Hepatitis
Hemic/Lymphatic
Agranulocytosis
Prolongation of Prothrombin Time
Petechia
Metabolic/Nutritional
Hyperglycemia
Hypoglycemia
Musculoskeletal
Arthralgia
Joint Stiffness
Muscle Weakness
Renal/Urogenital
Renal Failure
Interstitial Nephritis
Hemorrhagic Cystitis
Renal Calculi
Frequent Urination
Gynecomastia
Crystalluria
Cylindruria
Hematuria
Albuminuria
Respiratory
Respiratory Arrest
Dyspnea
Laryngeal Edema
Hemoptysis
Bronchospasm
Skin/Hypersensitivity
Allergic Reactions
Anaphylactic Reactions including life-threatening anaphylactic
shock
Erythema Multiforme/Stevens-Johnson Syndrome
Exfoliative Dermatitis
Toxic Epidermal Necrolysis
Vasculitis
Angioedema
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System Organ Class
Adverse Reactions
extremities
Purpura
Fever
Pruritus
Urticaria
Increased Perspiration
Erythema Nodosum
Thrombophlebitis
Burning
Photosensitivity/Phototoxicity Reaction
Special Senses
Decreased Visual Acuity
Blurred Vision
Disturbed Vision (diplopia, chromatopsia, and photopsia)
Anosmia
Hearing Loss
Tinnitus
Nystagmus
Bad Taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing CIPRO (Intravenous and
Intravenous/Oral. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction
profile of CIPRO was comparable to that of the control drugs.
Pediatric Patients
Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous
ciprofloxacin was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration
of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A
total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6
weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal
adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually
within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution
of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse
reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse
reactions was consistently higher in the ciprofloxacin group compared to the control group across all age
subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period
was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated
patients (Table 6).
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Table 6: Musculoskeletal Adverse Reactions1 as Assessed by the IPSC
CIPRO
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval2
(-0.8%, +7.2%)
Age Group
12 months to 24 months
1/36 (2.8%)
0/41
2 years to <6 years
5/124 (4%)
3/118 (2.5%)
6 years to <12 years
18/143 (12.6%)
12/153 (7.8%)
12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval2
(-0.6%, + 9.1%)
1.
Included: arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain,
myalgia, arm pain, and decreased range of motion in a joint (knee, elbow, ankle, hip, wrist, and shoulder)
2.
The study was designed to demonstrate that the arthropathy rate for the CIPRO group did not exceed that of the control
group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could
not be concluded that the ciprofloxacin group had findings comparable to the control group.
The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness,
nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were
41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most
frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9%
(31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse
reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%,
vomiting 4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for
the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5–17 years). Sixty seven
patients received CIPRO IV 10 mg/kg/dose every 8 hours for one week followed by CIPRO tablets 20
mg/kg/dose every 12 hours to complete 10–21 days treatment and 62 patients received the combination of
ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8
hours for a total of 10–21 days. Periodic musculoskeletal assessments were conducted by treatment-
blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0–
93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin
group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects
in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the
patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were
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similar in nature and frequency between treatment arms. The efficacy of CIPRO for the treatment of acute
pulmonary exacerbations in pediatric cystic fibrosis patients has not been established.
In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected
that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur
in pediatric patients.
6.2 Postmarketing Experience
The following adverse reactions have been reported from worldwide marketing experience with
fluoroquinolones, including CIPRO IV. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure (Table 7).
Table 7: Postmarketing Reports of Adverse Drug Reactions
System Organ Class
Adverse Reactions
Cardiovascular
QT prolongation
Torsade de Pointes
Vasculitis and ventricular arrhythmia
Central Nervous System
Hypertonia
Myasthenia
Exacerbation of myasthenia gravis
Peripheral neuropathy
Polyneuropathy
Twitching
Eye Disorders
Nystagmus
Gastrointestinal
Pseudomembranous colitis
Hemic/Lymphatic
Pancytopenia (life threatening or fatal outcome)
Methemoglobinemia
Hepatobiliary
Hepatic failure (including fatal cases)
Infections and Infestations
Candidiasis (oral, gastrointestinal, vaginal)
Investigations
Prothrombin time prolongation or decrease
Cholesterol elevation (serum)
Potassium elevation (serum)
Musculoskeletal
Myalgia
Myoclonus
Tendinitis
Tendon rupture
Psychiatric Disorders
Agitation
Confusion
Delirium
Skin/Hypersensitivity
Acute generalize exanthematous pustulosis
(AGEP)
Fixed eruption
Serum sickness-like reaction
Special Senses
Anosmia
Hyperesthesia
Hypesthesia
Taste loss
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6.3 Adverse Laboratory Changes
Changes in laboratory parameters while on CIPRO IV therapy are listed below:
• Hepatic-Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin
• Hematologic-Elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
• Renal-Elevations of serum creatinine, BUN, and uric acid
• Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring were: decreased leukocyte count, elevated atypical lymphocyte count, immature
WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT), decreased
BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum
potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring during
administration of ciprofloxacin were: elevation of serum amylase, decrease of blood glucose,
pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased
prothrombin time, hemolytic anemia, and bleeding diathesis.
7 DRUG INTERACTIONS
Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co
administration of CIPRO IV with other drugs primarily metabolized by CYP1A2 results in increased
plasma concentrations of these drugs and could lead to clinically significant adverse events of the co
administered drug.
Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and CIPRO IV
is contraindicated due to the potentiation of hypotensive
and sedative effects of tizanidine [see Contraindications
(4.2)]
Theophylline
Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of CIPRO IV with
theophylline may result in increased risk of a patient
developing central nervous system (CNS) or other
adverse reactions. If concomitant use cannot be avoided,
monitor serum levels of theophylline and adjust dosage
as appropriate. [See Warnings and Precautions (5.6).]
Drugs Known to
Prolong QT Interval
Avoid Use
CIPRO IV may further prolong the QT interval in
patients receiving drugs known to prolong the QT
interval (for example, class IA or III antiarrhythmics,
tricyclic antidepressants, macrolides, antipsychotics)
[see Warnings and Precautions (5.10) and Use in
Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution
Glucose-lowering effect
Hypoglycemia sometimes severe has been reported
when CIPRO IV and oral antidiabetic agents, mainly
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Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
potentiated
sulfonylureas (for example, glyburide, glimepiride),
were co-administered, presumably by intensifying the
action of the oral antidiabetic agent. Fatalities have been
reported. Monitor blood glucose when ciprofloxacin is
co-administered with oral antidiabetic drugs. [See
Adverse Reactions (6.1).]
Phenytoin
Use with caution
Altered serum levels of
phenytoin (increased and
decreased)
To avoid the loss of seizure control associated with
decreased phenytoin levels and to prevent phenytoin
overdose-related adverse reactions upon CIPRO IV
discontinuation in patients receiving both agents,
monitor phenytoin therapy, including phenytoin serum
concentration during and shortly after co-administration
of CIPRO IV with phenytoin.
Cyclosporine
Use with caution
(transient elevations in serum
creatinine)
Monitor renal function (in particular serum creatinine)
when ciprofloxacin is co-administered with
cyclosporine.
Anti-coagulant drugs
Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and
general status of the patient so that the contribution of
CIPRO IV to the increase in INR (international
normalized ratio) is difficult to assess. Monitor
prothrombin time and INR frequently during and shortly
after co-administration of CIPRO IV with an oral anti
coagulant (for example, warfarin).
Methotrexate
Use with caution
Inhibition of methotrexate renal
tubular transport potentially
leading to increased
methotrexate plasma levels
Potential increase in the risk of methotrexate associated
toxic reactions. Therefore, carefully monitor patients
under methotrexate therapy when concomitant CIPRO
IV therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and
appropriate dose adjustment of ropinirole is
recommended during and shortly after co-administration
with CIPRO IV [see Warnings and Precautions (5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse
reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with
CIPRO IV are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl
salicylic acid) in combination of very high doses of
quinolones have been shown to provoke convulsions in
pre-clinical studies and in postmarketing.
Sildenafil
Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity (see Pharmacokinetics
12.3).
Duloxetine
Avoid Use
Five-fold increase in duloxetine
exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Use with caution
CIPRO IV inhibits the formation of paraxanthine after
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Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
Derivatives
Reduced clearance resulting in
elevated levels and prolongation
of serum half-life
caffeine administration (or pentoxifylline containing
products). Monitor for xanthine toxicity and adjust dose
as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid
Use with caution
(interferes with renal tubular
secretion of CIPRO and
increases CIPRO serum levels)
Potentiation of CIPRO IV toxicity may occur.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. CIPRO IV should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An
expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the
Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a
substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that
there is no risk.2
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3 In utero exposure to
fluoroquinolones during embryogenesis was not associated with increased risk of major malformations.
The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6%
for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).4 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were
both within background incidence ranges. No specific patterns of congenital abnormalities were found.
The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.2, 3 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses.
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3
times the maximum daily human dose based upon body surface area, respectively) and have revealed no
evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100
mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body
surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
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administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed.
8.3 Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is
unknown. Because of the potential risk of serious adverse reactions (including articular damage) in
infants nursing from mothers taking CIPRO IV, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Although effective in clinical trials, CIPRO IV is not a drug of first choice in the pediatric population due
to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO IV,
cause arthropathy in juvenile animals [see Warnings and Precautions (5.11) and Nonclinical Toxicology
(13.2)].
Complicated Urinary Tract Infection and Pyelonephritis
CIPRO IV is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric
patients 1 to 17 years of age. Although effective in clinical trials, CIPRO IV is not a drug of first choice in
the pediatric population due to an increased incidence of adverse reactions compared to the controls,
including events related to joints and/or surrounding tissues. [See Adverse Reactions (6.1) and Clinical
Studies (14.2).]
Inhalational Anthrax (Post-Exposure)
CIPRO IV is indicated in pediatric patients from birth to 17 years of age for inhalational anthrax (post
exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients
is appropriate [see Dosage and Administration (2.2) and Clinical Studies (14.3)].
Plague
CIPRO IV is indicated in pediatric patients from birth to 17 years of age, for treatment of plague,
including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague.
Efficacy studies of CIPRO IV could not be conducted in humans with pneumonic plague for feasibility
reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The
risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate. [See
Indications and Usage (1.12), Dosage and Administration (2.2), and Clinical Studies (14.4).]
8.5 Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture
when being treated with a fluoroquinolone such as CIPRO IV. This risk is further increased in patients
receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand,
shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to
several months after fluoroquinolone treatment have been reported. Caution should be used when
prescribing CIPRO IV to elderly patients especially those on corticosteroids. Patients should be informed
of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider
if any symptoms of tendinitis or tendon rupture occur. [See Boxed Warning, Warnings and Precautions
(5.1), and Adverse Reactions (6.2).]
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In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over
3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and
10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but greater sensitivity of
some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal function by virtue
of their advanced age, care should be taken in dose selection for elderly patients, and renal function
monitoring may be useful in these patients. [See Dosage and Administration (2.3) and Clinical
Pharmacology (12.3).]
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO IV with concomitant drugs that can result in
prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). [See
Warnings and Precautions (5.10).]
8.6 Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. [See Dosage and Administration (2.3) and Clinical Pharmacology (12.3).]
8.7 Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients
with acute hepatic insufficiency, have not been studied.
10 OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Observe the
patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and
acidify, if required, to prevent crystalluria. Adequate hydration must be maintained. Only a small amount
of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125mg/kg and 300 mg/kg.
11 DESCRIPTION
CIPRO IV (ciprofloxacin) is a synthetic antimicrobial agent for intravenous (IV) administration.
Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3
quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
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structural formula
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions
are available as sterile 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. CIPRO IV
contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is not made with natural rubber latex.. Solutions in contact with the plastic container
can leach out certain of its chemical components in very small amounts within the expiration period, for
example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has
been confirmed in tests in animals according to USP biological tests for plastic containers as well as by
tissue culture toxicity studies.
The glucose content for the 200 mL flexible container is 10 g.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].
12.3 Pharmacokinetics
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg CIPRO IV to normal volunteers, the
mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively (Table 9).
Table 9: Steady-state Ciprofloxacin Serum Concentrations (mcg/mL)
After 60-minute INTRAVENOUS Infusions every 12 hours.
Time after starting the infusion
Dose
30 minutes
1 hour
3 hour
6 hour
8 hour
12 hour
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose
on an every 12 hour regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by
first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12
hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to
that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state
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equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg intravenous dose
results in a C max similar to that observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given
every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours
(Table 10).
Table 10: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous
Doses
Parameters
500 mg
400 mg
750 mg
400 mg
every 12 hours
every 12 hours,
every 12 hours,
every 8
AUC (mcg•hr/mL)
Orally.
13.71
intravenously
12.71
orally
31.62
hours,
32.93
Cmax (mcg/mL)
2.97
4.56
3.59
4.07
1.
AUC 0-12h
2.
AUC 24h = AUC 0-12h x 2
3.
AUC 24h = AUC 0-8h x 3
Distribution
After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue
concentrations often exceed serum concentrations in both men and women, particularly in genital tissue
including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions,
mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into
the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism
After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The metabolites have
antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other
drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and
could lead to clinically significant adverse events of the co-administered drug [see Contraindications
(4.2), Warnings and Precautions (5.6, 5.15) Drug Interactions (7)].
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg intravenous dose, concentrations in the urine usually exceed 200
mcg/mL 0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing.
Following a 400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after
dosing and are usually greater than 30 mcg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (<less than1%) is recovered from the
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bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5
days after dosing.
Specific Populations
Elderly
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older
than 65 years) as compared to young adults. Although the Cmax is increased 16% to40%, the increase in
mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in
the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. [See Use in Specific Populations (8.5).]
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required [see Use in Specific Populations (8.6), Dosage and Administration (2.3)].
Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute
hepatic insufficiency, have not been fully studied.
Pediatrics
Following a single oral dose of 10 mg/kg CIPRO suspension to 16 children ranging in age from 4 months
to 7 years, the mean C max was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2
mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*hr/mL). There was no apparent age-dependence, and no
notable increase in C max or AUC upon multiple dosing (10 mg/kg three times a day). In children with
severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean C max
was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2
mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The
AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32.0 mcg*hr/mL) and 16.5 mcg*hr/mL
(range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective age groups. These values are within the
range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 hours–5 hours,
and the bioavailability of the oral suspension is approximately 60%.
Drug-Drug Interactions
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly
increased (C max 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500
mg twice a day for 3 days). Concomitant administration of tizanidine and CIPRO IV is
contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see
Contraindications (4.2)].
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Ropinirole
In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once
daily with 500 mg CIPRO twice-daily, the mean C max and mean AUC of ropinirole were increased by
60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose
adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see
Warnings and Precautions (5.15)].
Clozapine
Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum
concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively.
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with CIPRO IV are advised.
Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to
healthy subjects, the mean C max and mean AUC of sildenafil were both increased approximately two-fold.
Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in
the exposure of sildenafil upon co-administration of CIPRO IV.
Duloxetine
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the
CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold
increase in mean C max of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg
ciprofloxacin twice daily resulted in an increase of lidocaine C max and AUC by 12% and 26%,
respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible
interaction with CIPRO IV and an increase in adverse reactions related to lidocaine may occur upon
concomitant administration.
12.4 Microbiology
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA
replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones
occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or
drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to
ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6
.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
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Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro
and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Bacillus anthracis
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative bacteria
Citrobacter koseri
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Yersinia pestis
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of
the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to
the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in
treating clinical infections due to these bacteria has not been established in adequate and well-controlled
clinical trials.
Gram-positive bacteria
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
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Gram-negative bacteria
Acinetobacter lwoffi
Aeromonas hydrophila
Edwardsiella tarda
Enterobacter aerogenes
Klebsiella oxytoca
Legionella pneumophila
Pasteurella multocida
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility
test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports
that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports
should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.
The MICs should be determined using a standardized test method (broth and/or agar).5, 6, 7 The MIC
values should be interpreted according to criteria provided in Table 10.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the
susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a
standardized test method.6, 7, 8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to
test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in
Table 11.
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Table 11: Susceptibility Test Interpretive Criteria for Ciprofloxacin
MIC (mcg/mL)
Zone Diameter (mm)
Bacteria
S
I
R
S
I
R
Enterobacteriaceae
≤1
2
≥4
≥21
16–20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus aureus
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus epidermidis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus saprophyticus
≤1
2
≥4
≥21
16–20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16–20
≤15
Haemophilus influenzae1
≤1
-
-
≥21
-
-
Haemophilus parainfluenzae1
≤1
-
-
≥21
-
-
Streptococcus pneumoniae
≤1
2
≥4
≥21
16–20
≤15
Streptococcus pyogenes
≤1
2
≥4
≥21
16–20
≤15
Bacillus anthracis1
≤0.25
-
-
-
-
-
Yersinia pestis1
≤0.25
-
-
-
-
-
S=Susceptible, I=Intermediate, and R=Resistant.
1.
The current absence of data on resistant isolates precludes defining any results other than “Susceptible”. If isolates yield
MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the
antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of
the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if
the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be
repeated. This category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be used. This category also
provides a buffer zone that prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to
inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy
and precision of supplies and reagents used in the assay, and the techniques of the individuals performing
the test.5, 6, 7, 8 Standard ciprofloxacin powder should provide the following range of MIC values noted in
Table 12. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 12 should be
achieved.
Table 12: Acceptable Quality Control Ranges for Ciprofloxacin
Bacteria
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03
34–42
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC 29213
0.12–0.5
-
Staphylococcus aureus ATCC 25923
-
22–30
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A total of 8 in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are
listed below:
• Salmonella/Microsome Test (Negative)
• E. coli DNA Repair Assay (Negative)
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V 79 Cell HGPRT Test (Negative)
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerevisiae Point Mutation Assay (Negative)
• Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte DNA Repair Assay (Positive)
• Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due
to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively
(approximately 1.7- times and 2.5- times the highest recommended therapeutic dose based upon body
surface area, respectively).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon body surface area), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to32 weeks
in mice treated concomitantly with UVA and other quinolones.9
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no
data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times
the highest recommended therapeutic dose based upon body surface area) revealed no evidence of
impairment.
13.2 Animal Toxicology and/or Pharmacology
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested [see Warnings and Precautions (5.11)].
Damage of weight-bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30
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mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral
ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- times and 3.5-times the
pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes
which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg
(approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints
were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free
period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did
not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon body
surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release, since they
are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection
also produces hypotension but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and
indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals
14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of CIPRO IV, 400 mg intravenously every 8 hours, in combination with
piperacillin sodium, 50 mg/kg intravenously every 4 hours, for the empirical therapy of febrile
neutropenic patients were studied in one large pivotal multicenter, randomized trial and were compared to
those of tobramycin, 2 mg/kg intravenously every 8 hours, in combination with piperacillin sodium, 50
mg/kg intravenously every 4 hours.
Clinical response rates observed in this study were as follows:
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 13.
Table 13: Clinical Response Rates
Outcomes
CIPRO IV/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of Initial
63 (27%)
52 (21.9%)
Febrile Episode with No
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Modifications of Empirical
Regimen1
Clinical Resolution of Initial
187 (80.3%)
185 (78.1%)
Febrile Episode Including
Patients with Modifications of
Empirical Regimen
Overall Survival
224 (96.1%)
185 (78.1%)
1.
To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological eradication of
infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of infection; and (4) no
modification of empirical antibiotic regimen
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in Pediatric
Patients
Ciprofloxacin, administered IV and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 14.
Table 14: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment1
84.4% (178/211)
78.3% (181/231)
95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
1.
Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were
5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.
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14.3 Inhalational Anthrax in Adults and Pediatrics
Additional information
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in
survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been
evaluated in various human populations. The mean peak serum concentration achieved at steady-state in
human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400
mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these
regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak
plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26
mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After
the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin
serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication.11
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5
x 105) spores (range 5-30 LD 50) of B. anthracis was conducted. The minimal inhibitory concentration
(MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied,
mean serum concentrations of ciprofloxacin achieved at expected T max (1 hour post-dose) following oral
dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL.10 Mortality due to
anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-
exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.11
More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were
also given anthrax vaccine or were switched to alternative antibacterial drugs. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
14.4 Plague
A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110
LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean
peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49
mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day
6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day
6 and Day 10) were < 0.5 mcg/mL. Animals were randomized to receive either a 10-day regimen of
intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body
temperature greater than 1.5oC over baseline for two hours), or at 76 hours post-challenge, whichever
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occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the
placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one
ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure
of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all
timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of
low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was
negative.12
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9. CReport presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory
Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER,
Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852,
USA.
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therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for
treatment of Pneumonic Plague.
16 HOW SUPPLIED/STORAGE AND HANDLING
CIPRO IV (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution in flexible
containers not made with natural rubber latex.
SIZE
STRENGTH
NDC NUMBER
200 mL
5% Dextrose 400 mg, 0.2%
50419-759-01
STORAGE
Store between 5–25ºC (41–77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-Approved patient labeling (Medication Guide)
Antibacterial Resistance
Inform patients that antibacterial drugs including CIPRO IV should only be used to treat bacterial
infections. They do not treat viral infections (for example, the common cold). When CIPRO IV prescribed
to treat a bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing
the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable by CIPRO IV or other
antibacterial drugs in the future.
Administration
Inform patients to drink fluids liberally while taking CIPRO to avoid formation of highly concentrated
urine and crystal formation in the urine.
Serious and Potentially Serious Adverse Reactions
Inform patients of the following serious adverse reactions that have been associated with CIPRO or other
fluoroquinolone use:
• Tendon Disorders Instruct patients to contact their healthcare provider if they experience pain,
swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and
refrain from exercise; and discontinue CIPRO treatment. The risk of severe tendon disorder with
fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of
myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of
muscle weakness, including respiratory difficulties.
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• Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions,
even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other
skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting
angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or
other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events)
has been reported in patients taking CIPRO IV. Instruct patients to inform their physician if they
experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever,
weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light
colored bowel movements or dark colored urine.
• Convulsions: Inform patients that convulsions have been reported in patients receiving
fluoroquinolones, including ciprofloxacin. Instruct patients to notify their physician before taking this
drug if they have a history of convulsions.
• Neurologic Adverse Effects (for example, dizziness, lightheadedness, increased intracranial
pressure): Inform patients that they should know how they react to CIPRO IV before they operate an
automobile or machinery or engage in other activities requiring mental alertness and coordination.
Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop
watery and bloody stools (with or without stomach cramps and fever) even as late as two or more
months after having taken the last dose of the antibiotic. If this occurs, Instruct patients to contact
their physician as soon as possible.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with
ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible If
symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, immediately discontinue CIPRO IV and contact their physician.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or
family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or
recent myocardial ischemia if they are taking any Class IA (quinidine, procainamide), or Class III
(amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have
any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of
consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician
if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric
patients to notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.4)].
• Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine.
Ciprofloxacin increases the effects of tizanidine (Zanaflex®).
• Theophylline: Inform patients that ciprofloxacin CIPRO IV may increase the effects of theophylline.
Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek
medical help if they experience seizures, palpitations, or difficulty breathing.
• Caffeine: Inform patients that ciprofloxacin may increase the effects of caffeine. There is a
possibility of caffeine accumulation when products containing caffeine are consumed while taking
quinolones.
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• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported
in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or
artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be
outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun
exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or
skin eruption occurs, instruct patients to contact their physician.
Drug Interactions Oral Antidiabetic Agents
Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were
co-administered; if low blood sugar occurs with CIPRO IV, instruct them toconsult their physician and
that their antibacterial medicine may need to be changed.
Anthrax and Plague Studies
Inform patients given CIPRO IV for this condition that efficacy studies could not be conducted in humans
for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies
conducted in animals.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
for oral suspension
CIPRO® XR (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® IV (Sip-row)
(ciprofloxacin)
Injection
for intravenous infusion
Read this Medication Guide before you start taking CIPRO and each time you get a
refill. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO, a fluoroquinolone antibacterial medicine, can cause serious side
effects. Some of these serious side effects could result in death.
If you get any of the following serious side effects while you take CIPRO, get
medical help right away. Talk with your healthcare provider about whether you
should continue to take CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis).
•
Tendon problems can happen in people of all ages who take CIPRO.
Tendons are tough cords of tissue that connect muscles to bones.
Symptoms of tendon problems may include:
o pain
o swelling
o tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
• The risk of getting tendon problems while you take CIPRO is higher if
you:
o are over 60 years of age
o are taking steroids (corticosteroids)
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o have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO.
• Other reasons that can increase your risk of tendon problems can include:
o physical activity or exercise
o kidney failure
o tendon problems in the past, such as in people with rheumatoid arthritis
(RA)
• Call your healthcare provider right away at the first sign of tendon
pain, swelling or inflammation. Stop taking CIPRO until tendinitis or
tendon rupture has been ruled out by your healthcare provider. Avoid
exercise and using the affected area.
The most common area of pain and swelling is the Achilles tendon at the
back of your ankle. This can also happen with other tendons. Talk to your
healthcare provider about the risk of tendon rupture with continued use of
CIPRO. You may need a different antibiotic that is not a fluoroquinolone to
treat your infection.
• Tendon rupture can happen while you are taking or after you have
finished taking CIPRO. Tendon ruptures have happened up to several
months after people have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or
symptoms of a tendon rupture:
o hear or feel a snap or pop in a tendon area
o bruising right after an injury in a tendon area
o unable to move the affected area or bear weight
2. Worsening of myasthenia gravis (a problem that causes muscle
weakness). Fluoroquinolones like CIPRO may cause worsening of myasthenia
gravis symptoms, including muscle weakness and breathing problems. Call your
healthcare provider right away if you have any worsening muscle weakness or
breathing problems.
See “What are the possible side effects of CIPRO?”
What is CIPRO?
CIPRO is a fluoroquinolone antibacterial medicine used in adults age 18 years and
older to treat certain infections caused by certain germs called bacteria. These
bacterial infections include:
• urinary tract infection
• chronic prostate infection
• lower respiratory tract infection
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• sinus infection
• skin infection
• bone and joint infection
• nosocomial pneumonia
• intra-abdominal infection, complicated
• infectious diarrhea
• typhoid (enteric) fever
• cervical and urethral gonorrhea, uncomplicated
• people with a low white blood cell count and a fever
• inhalational anthrax
• plague
• Studies of CIPRO for use in the treatment of plague and anthrax were done in
animals only, because plague and anthrax could not be studied in people.
• CIPRO is also used in children younger than 18 years of age to treat
complicated urinary tract and kidney infections or who may have breathed in
anthrax germs, have plague or have been exposed to plague germs.
• Children younger than 18 years of age have a higher chance of getting bone,
joint, or tendon (musculoskeletal) problems such as pain or swelling while taking
CIPRO. CIPRO should not be used as the first choice of antibacterial medicine in
children under 18 years of age.
• CIPRO XR is only used in adults 18 years of age and older to treat urinary
tract infections (complicated and uncomplicated), including kidney infections
(pyelonephritis).
• It is not known if CIPRO XR is safe and effective in children under 18 years of
age.
Who should not take CIPRO?
Do not take CIPRO if you:
• Have ever had a severe allergic reaction to an antibacterial medicine known as a
fluoroquinolone, or are allergic to ciprofloxacin hydrochloride or any of the
ingredients in CIPRO. See the end of this Medication Guide for a complete list of
ingredients in CIPRO.
•
Also take a medicine called tizanidine (Zanaflex®).
Ask your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking CIPRO?
Before you take CIPRO, tell your healthcare provider if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis)
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• have liver problems
• have central nervous system problems (such as epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition
called “QT prolongation”
• have or have had seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do
not work well.
• have joint problems including rheumatoid arthritis (RA)
• have trouble swallowing pills
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if CIPRO will harm
your unborn baby.
• are breastfeeding or plan to breastfeed. CIPRO passes into breast milk. You and
your healthcare provider should decide whether you will take CIPRO or
breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
CIPRO and other medicines can affect each other causing side effects.
Especially tell your healthcare provider if you take:
• a steroid medicine
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• theophylline (such as Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• a medicine to control your heart rate or rhythm (antiarrhythmics)
• an oral anti-diabetes medicine
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin® ,
Extended Phenytoin Sodium®, Prompt Phenytoin Sodium®, Phenytek®)
• cyclosporine (Gengraf®, Neoral®, Sandimmune®, Sangcya®).
• a blood thinner (such as warfarin, Coumadin®, Jantoven®)
• methotrexate (Trexall®)
• ropinirole (Requip®)
• clozapine (Clozaril®, Fazaclo® ODT®)
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• a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many common medicines for
pain relief are NSAIDs. Taking an NSAID while you take CIPRO or other
fluoroquinolones may increase your risk of central nervous system effects and
seizures.
• sildenafil (Viagra®, Revatio®)
• duloxetine
• products that contain caffeine
• probenecid (Probalan®, Col-probenecid ®)
• certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from
working correctly. Take CIPRO Tablets and Oral Suspension either 2 hours
before or 6 hours after taking these medicines, vitamins, or supplements:
o an antacid, multivitamin, or other medicine or supplements that has
magnesium, calcium, aluminum, iron, or zinc
o sucralfate (Carafate®)
o didanosine (Videx®, Videx EC®)
Ask your healthcare provider for a list of these medicines if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much CIPRO to take and when to take
it.
• Take CIPRO Tablets in the morning and evening at about the same time each
day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your
healthcare provider if you cannot swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time
each day. Shake the CIPRO Oral Suspension bottle well each time before use for
about 15 seconds to make sure the suspension is mixed well. Close the bottle
completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare
provider if you cannot swallow the tablet whole.
• CIPRO IV is given to you by intravenous (IV) infusion into your vein, slowly,
over 60 minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-
fortified juices alone, but may be taken with a meal that contains these
products.
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• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses of CIPRO, or stop taking it, even if you begin to feel
better, until you finish your prescribed treatment unless:
o you have tendon problems. See “What is the most important
information I should know about CIPRO?”
o you have a serious allergic reaction. See “What are the possible side
effects of CIPRO?”
o your healthcare provider tells you to stop taking CIPRO
Taking all of your CIPRO doses will help make sure that all of the bacteria are
killed. Taking all of your CIPRO doses will help lower the chance that the
bacteria will become resistant to CIPRO. If you become resistant to CIPRO,
CIPRO and other antibacterial medicines may not work for you in the future.
• If you take too much CIPRO, call your healthcare provider or get medical help
right away.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate
machinery, or do other activities that require mental alertness or coordination
until you know how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can
make your skin sensitive to the sun (photosensitivity) and the light from
sunlamps and tanning beds. You could get a severe sunburn, blisters or swelling
of your skin. If you get any of these symptoms while you take CIPRO, call your
healthcare provider right away. You should use a sunscreen and wear a hat and
clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
CIPRO may cause serious side effects, including:
• See, “What is the most important information I should know about
CIPRO?”
• Serious allergic reactions. Serious allergic reactions, including death, can
happen in people taking fluoroquinolones, including CIPRO, even after only 1
dose. Stop taking CIPRO and get emergency medical help right away if you get
any of the following symptoms of a severe allergic reaction:
o hives
o trouble breathing or swallowing
o swelling of the lips, tongue, face
o throat tightness, hoarseness
o rapid heartbeat
o faint
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o skin rash
Skin rash may happen in people taking CIPRO even after only 1 dose. Stop
taking CIPRO at the first sign of a skin rash and call your healthcare provider.
Skin rash may be a sign of a more serious reaction to CIPRO.
• Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who
take CIPRO. Call your healthcare provider right away if you have unexplained
symptoms such as:
o nausea or vomiting
o unusual tiredness
o stomach pain
o loss of appetite
o fever
o light colored bowel
movements
o weakness
o dark colored urine
o abdominal pain or
tenderness
o yellowing of your skin or the
whites of your eyes
o itching
Stop taking CIPRO and tell your healthcare provider right away if you have
yellowing of your skin or white part of your eyes, or if you have dark urine.
These can be signs of a serious reaction to CIPRO (a liver problem).
• Central Nervous System (CNS) effects. Seizures have been reported in
people who take fluoroquinolone antibacterial medicines, including CIPRO. Tell
your healthcare provider if you have a history of seizures. Ask your healthcare
provider whether taking CIPRO will change your risk of having a seizure.
CNS side effects may happen as soon as after taking the first dose of CIPRO.
Talk to your healthcare provider right away if you get any of these side effects,
or other changes in mood or behavior:
o seizures
o trouble sleeping
o hear voices, see things, or
o nightmares
sense things that are not there
o feel lightheaded or dizzy
(hallucinations)
o feel more suspicious (paranoia)
o feel restless
o suicidal thoughts or acts
o tremors
o headaches that will not go away,
o feel anxious or nervous
with or without blurred vision
o confusion
o depression
• Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen
with many antibacterial medicines, including CIPRO. Call your healthcare provider right away
if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have
stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after
you have finished your antibacterial medicine.
43
Reference ID: 3718341
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• Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage
to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones,
including CIPRO. Talk with your healthcare provider right away if you get any of the following
symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
o pain
o burning
o tingling
o numbness
o weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Serious heart rhythm changes (QT prolongation and torsade de pointes). Tell your
healthcare provider right away if you have a change in your heart beat (a fast or irregular
heartbeat), or if you faint. CIPRO may cause a rare heart problem known as prolongation of
the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous.
The chances of this event are higher in people:
o who are elderly
o with a family history of prolonged QT interval
o with low blood potassium (hypokalemia)
o who take certain medicines to control heart rhythm (antiarrhythmics)
• Joint Problems. Increased chance of problems with joints and tissues around joints in
children under 18 years old can happen. Tell your child’s healthcare provider if your child has
any joint problems during or after treatment with CIPRO.
• Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking
CIPRO?”
The most common side effects of CIPRO include:
• nausea
• diarrhea
• changes in liver function tests
• vomiting
•
rash
Tell your healthcare provider about any side effect that bothers you, or that does not go away.
These are not all the possible side effects of CIPRO. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1
800-FDA-1088.
How should I store CIPRO?
CIPRO Tablets
•
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
CIPRO Oral Suspension
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• Store microcapsules and diluent below 25°C (77°F); excursions are permitted from 15°C
to 30°C (59°F to 86°F).
• Do not freeze.
• After your CIPRO treatment is finished, safely throw away any unused oral suspension.
CIPRO XR
• Store CIPRO XR between 59°F to 86°F (15°C to 30°C).
Keep CIPRO and all medicines out of the reach of children.
General Information about the safe and effective use of CIPRO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would
like more information about CIPRO, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about CIPRO that is written for healthcare
professionals.
For more information call 1-888-842-2937.
What are the ingredients in CIPRO?
CIPRO Tablets:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene
glycol
CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients:
o Microcapsules contains: povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20
o Diluent contains: medium-chain triglycerides, sucrose, soy-lecithin, water, and
strawberry flavor
CIPRO XR:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide
CIPRO IV:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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This label may not be the latest approved by FDA.
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Manufactured for: company logo
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
©2015 Bayer HealthCare Pharmaceuticals Inc.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Manufactured in Italy
CIPRO (ciprofloxacin HCl) Tablets Manufactured in Germany
Revised: March 2015
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|
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2025-02-12T13:46:09.037411
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LOTENSIN safely and effectively. See full prescribing information for
use LOTENSIN.
LOTENSIN (benazepril hydrochloride) tablets, for oral use
Initial U.S. Approval: 1991
WARNING- FETAL TOXICITY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue Lotensin as soon as possible.
(5.1)
Drugs that act directly on the renin-angiotensin system can cause
injury and death to the developing fetus. (5.1)
----------------------------INDICATIONS AND USAGE---------------------------
Lotensin is an angiotensin-converting enzyme (ACE) inhibitor indicated
for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular
events, primarily strokes and myocardial infarctions. (1)
--------------------DOSAGE AND ADMINISTRATION------------------------
• Adult Patients: Initiate with 10 mg once daily (or 5 mg if patient is on
diuretic). Titrate to 40 mg daily based on blood pressure response. (2.1)
• Pediatric patients age 6 years and above with glomerular filtration rate
(GFR) >30 mL/min/1.73 m2: Initiate with 0.2 mg/kg once daily.
Maximum dose is 0.6 mg/kg once daily.
• Renal Impairment: Initiate with 5 mg once daily in patients with GFR <30
mL/min/1.73 m2 (serum creatinine >3 mg/dL) (2.3)
-----------------DOSAGE FORMS AND STRENGTHS-------------------------
• Tablets: 5 mg, 10 mg, 20 mg, 40 mg
-------------------------------CONTRAINDICATIONS----------------------------
• Angioedema or history of hereditary or idiopathic angioedema (4)
• Hypersensitivity (4)
• Co-administration with aliskiren in patients with diabetes (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------
• Angioedema: Discontinue Lotensin and treat appropriately. (5.2)
• Monitor renal function periodically. (5.3)
• Monitor blood pressure after initiation. (5.4)
• Hyperkalemia: Monitor serum potassium periodically. (5.5)
• Hepatic toxicity: Monitor for jaundice or signs of liver failure. (5.6)
---------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions leading to discontinuation were headache
(0.6%) (5.6) and cough (5.7)
To report SUSPECTED ADVERSE REACTIONS, contact Validus
Pharmaceuticals LLC at 1-866-9VALIDUS or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------DRUG INTERACTIONS----------------------------------
•
Diuretics: Excessive drop in blood pressure (7.1)
•
Antidiabetics: Increased risk of hypoglycaemia (7.2)
•
NSAIDS: Increased risk of renal impairment and loss of antihypertensive
efficacy (7.3)
•
Dual inhibition of the renin-angiotensin system: Increased risk of renal
impairment, hypotension and hyperkalemia (7.4)
•
Lithium: Symptoms of lithium toxicity (7.5)
-------------------------USE IN SPECIFIC POPULATIONS---------------------
•
Pregnancy: Discontinue drug if pregnancy is detected (5.1, 8.1)
•
Pediatrics: Safety and effectiveness have not been established in patients
< 6 years of age or with GFR < 30 mL/min/1.73m2 (8.4)
•
Race: Less antihypertensive effect in blacks as monotherapy (8.6)
See 17 for PATIENT COUNSELING INFORMATION [and FDA-
approved patient labeling OR and Medication Guide].
Revised: 07/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended dosage
2.2 Dosage Adjustment for Renal Impairment
2.3 Preparation of Suspension (for 150 mL of a 2 mg/mL
Suspension)
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Fetal Toxicity
5.2 Angioedema and Anaphylactoid Reactions
5.3 Impaired Renal Function
5.4 Hypotension
5.5 Hyperkalemia
5.6 Hepatic Failure
5.7 Cough
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
7.1 Diuretics
7.2 Antidiabetics
7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
7.4 Dual Blockade of the Renin-Angiotensin System (RAS)
7.5 Mamalian Target of Rapamycin (mTOR) Inhibitors
7.6 Lithium
7.7 Gold
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Race
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3795436
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FULL PRESCRIBING INFORMATION
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue Lotensin as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. [see Warnings and Precautions (5.1)]
1.
INDICATIONS AND USAGE
Lotensin is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes
and myocardial infarctions. These benefits have been seen in controlled trials of
antihypertensive drugs from a wide variety of pharmacologic classes including the class to
which this drug principally belongs.
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more
than one drug to achieve blood pressure goals. For specific advice on goals and management, see
published guidelines, such as those of the National High Blood Pressure Education Program’s
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce
cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure
reduction, and not some other pharmacologic property of the drugs, that is largely responsible
for those benefits. The largest and most consistent cardiovascular outcome benefit has been a
reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular
mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
It may be used alone or in combination with thiazide diuretics.
Reference ID: 3795436
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2.
DOSAGE AND ADMINISTRATION
2.1.
Recommended Dosage
ADULTS
The recommended initial dose for patients not receiving a diuretic is 10 mg once a day. The
usual maintenance dosage range is 20 mg to 40 mg per day administered as a single dose or in
two equally divided doses. A dose of 80 mg gives an increased response, but experience with
this dose is limited. The divided regimen was more effective in controlling trough (pre-dosing)
blood pressure than the same dose given as a once-daily regimen.
Use with diuretics in adults
The recommended starting dose of Lotensin in a patient on a diuretic is 5 mg once daily. If blood
pressure is not controlled with Lotensin alone, a low dose of diuretic may be added.
PEDIATRIC PATIENTS 6 YEARS OF AGE AND OLDER
The recommended starting dose for pediatric patients is 0.2 mg/kg once per day. Titrate as
needed to 0.6 mg/kg once per day. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not
been studied in pediatric patients.
Lotensin is not recommended in pediatric patients less than 6 years of age or in pediatric patients
with GFR less than 30 mL/min/1.73m² [see Use in Specific Populations (8.2)].
2.2.
Dose Adjustment for Renal Impairment
For adults with a GFR <30 mL/min/1.73 m2 (serum creatinine >3 mg/dL), the recommended
initial dose is 5 mg Lotensin once daily. Dosage may be titrated upward until blood pressure is
controlled or to a maximum total daily dose of 40 mg. Lotensin can also worsen renal function
[see Warnings and Precautions (5.3)].
2.3.
Preparation of Suspension (for 150 mL of a 2 mg/mL Suspension)
Add 75 mL of Ora-Plus®* oral suspending vehicle to an amber polyethylene terephthalate (PET)
bottle containing fifteen Lotensin 20 mg tablets, and shake for at least two minutes. Allow the
suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a
minimum of one additional minute. Add 75 mL of Ora-Sweet®* oral syrup vehicle to the bottle
and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2
8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-
cap closure. Shake the suspension before each use.
*Ora-Plus® and Ora-Sweet® are registered trademarks of Paddock Laboratories, Inc. Ora Plus®
contains carrageenan, citric acid, methylparaben, microcrystalline cellulose,
carboxymethylcellulose sodium, potassium sorbate, simethicone, sodium phosphate monobasic,
xanthan gum, and water. Ora-Sweet® contains citric acid, berry citrus flavorant, glycerin,
methylparaben, potassium sorbate, sodium phosphate monobasic, sorbitol, sucrose, and water.
Reference ID: 3795436
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3.
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg, 10 mg, 20 mg, and 40 mg
• Each 5 mg tablet is light yellow with “5” on one side and “LOTENSIN” on the other
• Each 10 mg tablet is dark yellow with “10” on one side and “LOTENSIN” on the
other
• Each 20 mg tablet is pink with “20” on one side and “LOTENSIN” on the other
• Each 40 mg tablet is dark rose with “40” on one side and “LOTENSIN” on the other
4.
CONTRAINDICATIONS
Lotensin is contraindicated in patients:
• who are hypersensitive to benazapril or to any other ACE inhibitor
• with a history of angioedema with or without previous ACE inhibitor treatment
Do not co-administer aliskiren with Lotensin in patients with diabetes [see Drug Interactions
(7.4)].
5.
WARNINGS AND PRECAUTIONS
5.1.
Fetal Toxicity
PREGNANCY CATEGORY D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue Lotensin as soon as possible
[see Use in Specific Populations (8.1)].
5.2
Angioedema and Anaphylactoid Reactions
Angioedema
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx including some fatal
reactions, have occured in patients treated with Lotensin. Patients with involvement of the
tongue, glottis or larynx are likely to experience airway obstruction, especially those with a
history of airway surgery. Lotensin should be promptly discontinued and appropriate therapy
and monitoring should be provided until complete and sustained resolution of signs and
symptoms of angioedema has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor [see Contraindications (4)]. ACE inhibitors
have been associated with a higher rate of angioedema in Black than in non-Black patients.
Reference ID: 3795436
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Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of
rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk
for angioedema.
Intestinal Angioedema
Intestinal angioedema has occurred in patients treated with ACE inhibitors. These patients
presented with abdominal pain (with or without nausea or vomiting); in some cases there was no
prior history of facial angioedema and C-1 esterase levels were normal. In some cases, the
angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor.
Anaphylactoid Reactions
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE
inhibitors sustained life-threatening anaphylactoid reactions.
Anaphylactoid Reactions During Dialysis
Sudden and potentially life threatening anaphylactoid reactions have occured in some patients
dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such
patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid
reactions must be initiated. Symptoms have not been relieved by antihistamines in these
situations. In these patients, consideration should be given to using a different type of dialysis
membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been
reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
5.3
Impaired Renal Function
Monitor renal function periodically in patients treated with Lotensin. Changes in renal function,
including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin sytem.
Patients whose renal function may depend on the activity of the renin-angiotensin system (e.g.,
patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-
myocardial infarction, or volume depletion) may be at particular risk of developing acute renal
failure on Lotensin. Consider withholding or discontinuing therapy in patients who develop a
clinically significant decrease in renal function on Lotensin.
5.4 Hypotension
Lotensin can cause symptomatic hypotension, sometimes complicated by oliguria, progressive
azotemia acute renal failure or death. Patients at risk of excessive hypotension include those with
the following conditions or characteristics: heart failure with systolic blood pressure below 100
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mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic
therapy, renal dialysis, or severe volume and/or salt depletion of any etiology.
In such patients, follow closely for the first 2 weeks of treatment and whenever the dose of
benazepril or diuretic is increased. Avoid use of Lotensin in patients who are hemodynamically
unstable after acute MI.
Surgery/Anesthesia
In patients undergoing major surgery or during anesthesia with agents that produce hypotension,
Lotensin may block angiotensin II formation secondary to compensatory renin release. If
hypotension occurs, correct by volume expansion.
5.5
Hyperkalemia
Serum potassium should be monitored periodically in patients receiving Lotensin. Drugs that
inhibit the renin angiotensin system can cause hyperkalemia. Risk factors for the development of
hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes
[see Drug Interactions (7.1)].
5.6
Hepatic Failure
ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and
progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this
syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked
elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate
medical follow-up.
6
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
Lotensin has been evaluated for safety in over 6000 patients with hypertension; over 700 of these
patients were treated for at least one year. The overall incidence of reported adverse events was
similar in Lotensin and placebo patients.
The reported side effects were generally mild and transient, and there was no relation between
side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg.
Discontinuation of therapy because of a side effect was required in approximately 5% of U.S.
patients treated with Lotensin and in 3% of patients treated with placebo. The most common
reasons for discontinuation were headache (0.6%) and cough (0.5%)
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Adverse reactions seen in at least 1% greater frequency in patients treated with Lotensin than
placebo were headache (6% vs 4%), dizziness (4% vs 2%), somnolence (2% vs 0%) and postural
dizziness (2% vs 0%).
Adverse reactions reported in controlled clinical trials (less than 1% more on benazepril than on
placebo), and rarer events seen in post-marketing experience, include the following (in some, a
causal relationship to drug use is uncertain):
Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions
(manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
Gastrointestial: Nausea, pancreatitis, constipation, gastritis, vomiting, and melena.
Hematologic: Thrombocytopenia and hemolytic anemia.
Neurologic/Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and
paresthesia
Other: Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination,
infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating.
Laboratory Abnormalities:
Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes [see Warnings and
Precautions (6.5)] have been reported, as have incidents of hyponatremia, electrocardiographic
changes, eosinophilia, and proteinuria
7
DRUG INTERACTIONS
7.1
Diuretics
Hypotension
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may
occasionally experience an excessive reduction of blood pressure after initiation of therapy with
Lotensin. The possibility of hypotensive effects with Lotensin can be minimized by either
discontinuing or decreasing the dose of diuretic prior to initiation of treatment with Lotensin [see
Dosage and Administration (2.1)].
Hyperkalemia
otassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the
risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the
patient’s serum potassium frequently. Lotensin attenuates potassium loss caused by thiazide-type
diuretics.
7.2
Antidiabetics
Concomitant administration of Lotensin and antidiabetic medicines (insulins, oral hypoglycemic
agents) may increase the risk of hypoglycemia.
Reference ID: 3795436
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7.3
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2
Inhibitors (COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2
inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving benazepril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by
NSAIDs.
7.4
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is
associated with increased risks of hypotension, hyperkalemia, and changes in renal function
(including acute renal failure) compared to monotherapy. Most patients receiving the
combination of two RAS inhibitors do not obtain any additional benefit compared to
monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure,
renal function and electrolytes in patients on Lotensin and other agents that affect the RAS.
Do not co-administer aliskiren with Lotensin in patients with diabetes. Avoid use of aliskiren
with Lotensin in patients with renal impairment (GFR <60 ml/min).
7.5
Mammalian Target of Rapamycin (mTOR) Inhibitors
Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus,
sirolimus, everolimus) therapy may be at increased risk for angioedema. Monitor for signs of
angioedema [see Warnings and Precautions (5.2)].
7.6
Lithium
Lithium toxicity has been reported in patients receiving lithium concomitantly with Lotensin.
Lithium toxicity was usually reversible upon discontinuation of lithium or Lotensin. Monitor
serum lithium levels during concurrent use.
7.7
Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have
been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and
concomitant ACE inhibitor therapy.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category D
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Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue Lotensin as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third
trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure
to antihypertensive use in the first trimester have not distinguished drugs affecting the renin
angiotensin system from other antihypertensive agents. Appropriate management of maternal
hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue Lotensin, unless it is considered lifesaving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
Lotensin for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].
8.3
Nursing Mothers
Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast
milk of lactating women treated with benazepril. A newborn child ingesting entirely breast
milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and
benazeprilat.
8.4
Pediatric Use
The antihypertensive effects of Lotensin have been evaluated in a double-blind study in
pediatric patients 7 to 16 years of age [see Clinical Pharmacology (12.3)]. The
pharmacokinetics of Lotensin have been evaluated in pediatric patients 6 to 16 years of age
[see Clinical Pharmacology (12.3)].
Infants below the age of 1 year should not be given Lotensin because of the risk of effects on
kidney development.
Safety and effectiveness of Lotensin have not been established in pediatric patients less than
6 years of age or in children with glomerular filtration rate <30 mL/min/1.73m² [see Dosage
and Administration (2.1) and Clinical Pharmacology 12.3)].
Neonates with a history of in utero exposure to Lotensin:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Benazepril, which crosses the
Reference ID: 3795436
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placenta, can theoretically be removed from the neonatal circulation by these means; there
are occasional reports of benefit from these maneuvers with another ACE inhibitor, but
experience is limited.
8.5
Geriatric Use
Of the total number of patients who received benazepril in U.S. clinical studies of Lotensin,
18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or
safety were observed between these patients and younger patients, and other reported clinical
experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection, and
it may be useful to monitor renal function [see Dosage and Administration (2.2)].
8.6
Race
ACE inhibitors, including Lotensin, as monotherapy, have an effect on blood pressure that is less
in black patients than in non-blacks.
8.7
Renal Impairment
Dose adjustment of Lotensin is required in patients undergoing hemodialysis or whose creatinine
clearance is ≤30 mL/min. No dose adjustment of Lotensin is required in patients with creatinine
clearance >30 mL/min [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)].
10 OVERDOSAGE
Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice. Rats,
however, tolerated single oral doses of up to 6 g/kg. Reduced activity was seen at 1 g/kg in mice
and at 5 g/kg in rats. Human overdoses of benazepril have not been reported, but the most
common manifestation of human benazepril overdosage is likely to be hypotension, for which
the usual treatment would be intravenous infusion of normal saline solution. Hypotension can be
associated with electrolyte disturbances and renal failure.
Benazepril is only slightly dialyzable, but consider dialysis to support patients with severely
impaired renal function [see Warnings and Precautions (5.3)].
If ingestion is recent, consider activated charcoal. Consider gastric decontamination (e.g.,
vomiting, gastric lavage) in the early period after ingestion.
Monitor for blood pressure and clinical symptoms. Supportive management should be employed
to ensure adequate hydration and to maintain systemic blood pressure.
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In the case of marked hypotension, infuse physiological saline solution; as needed, consider
vasopressors (e.g., catecholamines i.v.).
11
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Its chemical name is benazepril 3-[[1-(ethoxy-carbonyl)-3
phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid
monohydrochloride; its structural formula is structural formula
Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting
enzyme inhibitor.
Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril
hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide,
crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron
oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80,
propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects
and animals. Benazeprilat has much greater ACE inhibitory activity than does benazepril.
ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the
vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion
by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in
a small increase of serum potassium.
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor
response to angiotensin II and did not interfere with the hemodynamic effects of the
autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
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ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels
of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of
Lotensin remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin hypertension.
12.2
Pharmacodynamics
Single and multiple doses of 10 mg or more of Lotensin cause inhibition of plasma ACE
activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to
exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg
dose.
Drug interactions
Lotensin has been used concomitantly with beta-adrenergic-blocking agents, calcium-
channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically
important adverse interactions. Benazepril, like other ACE inhibitors, has had less than
additive effects with beta-adrenergic blockers, presumably because both drugs lower blood
pressure by inhibiting parts of the renin-angiotensin system
12.3
Pharmacokinetics
The pharmacokinetics of benazepril are approximately dose-proportional within the dosage
range of 10-80 mg.
Following oral administration of Lotensin, peak plasma concentrations of benazepril, and its
active metabolite benazeprilat are reached within 0.5-1.0 hours and 1-2 hours, respectively.
While the bioavailability of benazepril is not affected by food, time to peak plasma
concentrations of benazeprilat is delayed to 2 – 4 hours.
The serum protein binding of benazepril is about 96.7% and that of benazeprilat about
95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of
protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the
concentration range of 0.24-23.6 µmol/L).
Benazepril is almost completely metabolized to benazeprilat by cleavage of the ester group
(primarily in liver). Both benazepril and benazeprilat undergo glucuronidation.
Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an
orally administered dose was recovered in urine as benazeprilat (20%), benazeprilat
glucuronide (8%), benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal
(i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion.. The
effective half-life of benazeprilat following once daily repeat oral administration of
benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat
should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.
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Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily
administration.
Specific Populations
Renal impairment
The pharmacokinetics of/ systemic exposure to benazepril and benazeprilat in patients with
mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in
patients with normal renal function. In patients with creatinine clearance ≤30 mL/min, peak
benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state
may be delayed (see DOSAGE AND ADMINISTRATION (2).
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6%
of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was
not detected in the dialysate.
Hepatic impairment
In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat
are essentially unaltered.
Drug Interactions
The pharmacokinetics of benazepril are not affected by the following drugs:
hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine,
amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of
benazepril does not substantially affect the pharmacokinetics of these medications
(cimetidine kinetics were not studied)
Pediatrics
The pharmacokinetics of benazaprilat, evaluated in pediatric patients with hypertension
following oral administration of a single dose is presented in table below.
Age group
Cmax
(ng/mL)
Tmax*
(h)
AUC0-inf
(ng/mL*h)
CL/F/wt
(L/h/Kg)
T1/2
(h)
>1 to ≤ 24 months
277
1
1328
0.26
5.0
n=5
(192, 391)
(0.6, 2)
(773, 2117)
(0.18, 0.4)
(4, 5.8)
>2 to ≤ 6 years
200
2
978
0.36
5.5
n=7
(168, 244)
(1.4, 2.4)
(842, 1152)
(0.31, 0.42)
(4.7, 6.5)
>6 to ≤ 12 years
221
2
1041
0.25
5.5
n=7
(194, 258)
(1.2, 2.2)
(855, 1313)
(0.21, 0.31)
(4.7, 6.5)
>12 to ≤ 17 years
287
2
1794
0.16
5.1
n=8
(217, 420)
(1.3, 2.3)
(1478, 2340)
(0.13, 0.21)
(4.2, 5.7)
Reference ID: 3795436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
NONCLINICAL TOXICOLOGY
13.1
Carciniogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was administered to rats and
mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of
body weights, this dose is 110 times the maximum recommended human dose. When
compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice,
respectively) the maximum recommended human dose (calculations assume a patient weight
of 60 kg). No mutagenic activity was detected in the Ames test in bacteria (with or without
metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells,
or in a nucleus anomaly test. In doses of 50-500 mg/kg/day (6-60 times the maximum
recommended human dose based on mg/m
2 comparison and 37-375 times the maximum
recommended human dose based on a mg/kg comparison), Lotensin had no adverse effect on
the reproductive performance of male and female rats.
14
CLINICAL STUDIES
Hypertension
Adult Patients
In single-dose studies, Lotensin lowered blood pressure within 1 hour, with peak reductions
achieved between 2 and 4 hours after dosing. The antihypertensive effect of a single dose
persisted for 24 hours. In multiple-dose studies, once-daily doses of between 20 mg and 80 mg
decreased seated pressure 24 hours after dosing by about 6 to 12mmHg systolic and 4 to 7
mmHg diastolic. The trough values represent reductions of about 50% of that seen at peak.
Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate
hypertensive patients not using diuretics. The minimal effective once-daily dose of Lotensin was
10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher
doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of
Lotensin given as a single morning dose or as a twice-daily dose, blood pressure reductions at
the time of morning trough blood levels were greater with the divided regimen.
The antihypertensive effects of Lotensin were not appreciably different in patients receiving
high- or low-sodium diets.
In normal human volunteers, single doses of benazepril caused an increase in renal blood flow
but had no effect on glomerular filtration rate.
Use of Lotensin in combination with thiazide diuretics gives a blood-pressure-lowering effect
greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone
axis, administration of Lotensin tends to reduce the potassium loss associated with the diuretic.
Pediatric Patients
Reference ID: 3795436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic
pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or
0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85
patients whose blood pressure was reduced on therapy were then randomized to either placebo or
benazepril and were followed up for an additional two weeks. At the end of two weeks, blood
pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg
more than in children on benazepril. No dose-response was observed.
16.
HOW SUPPLIED/STORAGE AND HANDLING
Lotensin is available as:
Dose
Color
Engraving
Bottle of 100
5 mg
Light
Yellow
Lotensin
5
NDC 30698-447-01
10 mg
Dark
Yellow
Lotensin
10
NDC 30698-448-01
20 mg
Pink
Lotensin
20
NDC 30698-449-01
40 mg
Dark
Rose
Lotensin
40
NDC 30698-450-01
Storage: Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Distributed by:
Validus Pharmaceuticals LLC
Parsippany, New Jersey 07054
info@validuspharma.com
www.validuspharma.com
1-866-9VALIDUS
© 2015 Validus Pharmaceuticals LLC
January 2015
17.
PATIENT COUNSELING INFORMATION
Pregnancy: Tell female patients of childbearing age about the consequences of exposure to
Lotensin during pregnancy. Discuss treatment options with women planning to become
pregnant. Instruct patients to report pregnancies to their physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. Tell patients to report immediately any signs or symptoms suggesting
angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no
more drug until they have consulted with the prescribing physician.
Reference ID: 3795436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Symptomatic Hypotension: Tell patients to report light-headedness especially during the
first few days of therapy. If actual syncope occurs, tell the patient to discontinue the drug
until they have consulted with the prescribing physician.
Tell patients that excessive perspiration and dehydration may lead to an excessive fall in
blood pressure because of a reduction in fluid volume. Other causes of volume depletion
such as vomiting or diarrhea may also lead to a fall in blood pressure; advise patients
accordingly.
Hyperkalemia: Tell patients not to use potassium supplements or salt substitutes containing
potassium without consulting the prescribing physician.
Hypoglycemia: Tell diabetic patients treated with oral antidiabetic agents or insulin starting
an ACE inhibitor to monitor for hypoglycemia closely, especially during the first month of
combined use.
Reference ID: 3795436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:09.089475
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019851s045s049lbl.pdf', 'application_number': 19851, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,786
|
CIPRO®
1
(ciprofloxacin hydrochloride)
2
TABLETS
3
CIPRO®
4
(ciprofloxacin*)
5
ORAL SUSPENSION
6
7
XXXXXXXX 3/25/04
8
9
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
10
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
11
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to
12
be caused by bacteria.
13
14
DESCRIPTION
15
CIPRO® (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
16
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
17
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-
18
dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow
19
crystalline
substance
with
a
molecular
weight
of
385.8.
Its
empirical
formula
is
20
C17H18FN3O3•HCl•H2O and its chemical structure is as follows:
21
22
23
24
25
26
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
27
acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish
28
to light yellow crystalline substance and its chemical structure is as follows:
29
30
31
32
33
34
CIPRO film-coated tablets are available in 100 mg, 250 mg, 500 mg and 750 mg (ciprofloxacin
35
equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients
36
are cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate,
37
hypromellose, titanium dioxide, polyethylene glycol and water.
38
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
39
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish
40
suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of
41
ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See instructions for
42
USE/HANDLING). The components of the suspension have the following compositions:
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Microcapsules - ciprofloxacin, povidone, methacrylic acid copolymer, hypromellose, magnesium
44
stearate, and Polysorbate 20.
45
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
46
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
47
CLINICAL PHARMACOLOGY
48
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the
49
gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with
50
no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area
51
under the curve are shown in the chart for the 250 mg to 1000 mg dose range.
52
53
Maximum
Area
54
Dose
Serum Concentration
Under Curve (AUC)
55
(mg)
(µg/mL)
(µg•hr/mL)
56
250
1.2
4.8
57
500
2.4
11.6
58
750
4.3
20.2
59
1000
5.4
30.8
60
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
61
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum
62
elimination half-life in subjects with normal renal function is approximately 4 hours. Serum
63
concentrations increase proportionately with doses up to 1000 mg.
64
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
65
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
66
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has
67
been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion
68
of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that
69
observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC
70
equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
71
72
Steady-state Pharmacokinetic Parameters
73
Following Multiple Oral and I.V. Doses
74
Parameters
500 mg
400 mg
750 mg
400
75
mg
76
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h,
77
I.V.
78
AUC (µg•hr/mL)
13.7a
12.7a
31.6b
32.9c
79
Cmax (µg/mL)
2.97
4.56
3.59
4.07
80
aAUC 0-12h
81
bAUC 24h=AUC0-12h x 2
82
cAUC 24h=AUC0-8h x 3
83
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be
84
high enough to cause significant protein binding interactions with other drugs.
85
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue
86
concentrations often exceed serum concentrations in both men and women, particularly in genital tissue
87
including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial
88
secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic
89
secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug
90
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10%
91
of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous
92
humors of the eye.
93
Metabolism: Four metabolites have been identified in human urine which together account for
94
approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active
95
than unchanged ciprofloxacin.
96
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
97
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
98
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL
99
during the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary
100
excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of
101
ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of
102
120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
103
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
104
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
105
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
106
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged
107
drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites.
108
Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This
109
may arise from either biliary clearance or transintestinal elimination.
110
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
111
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
112
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
113
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
114
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in
115
the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing
116
rather than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food.
117
The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected.
118
The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food.
119
Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may
120
reduce the bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
121
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
122
were given concomitantly.
123
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
124
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or
125
other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
126
paraxanthine after caffeine administration. (See PRECAUTIONS.)
127
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
128
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher
129
in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%,
130
the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased
131
renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly.
132
These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
133
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
134
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
135
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
136
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
137
acute hepatic insufficiency, however, have not been fully elucidated.
138
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from
139
4 months to 7 years, the mean Cmax was 2.4 mg/L (range: 1.5 – 3.4 mg/L) and the mean AUC was
140
9.2 mg*h/L (range: 5.8 – 14.9 mg*h/L). There was no apparent age-dependence, and no notable
141
increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who
142
were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mg/L
143
(range: 4.6 – 8.3 mg/L) in 10 children less than 1 year of age; and 7.2 mg/L (range: 4.7 – 11.8 mg/L)
144
in 10 children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range: 11.8 – 32.0
145
mg*h/L) and 16.5 mg*h/L (range: 11.0 – 23.8 mg*h/L) in the respective age groups. These values are
146
within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
147
analysis of pediatric patients with various infections, the predicted mean half-life in children is
148
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
149
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-
150
positive microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the
151
enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
152
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
153
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
154
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
155
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
156
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
157
by multiple step mutations.
158
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
159
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
160
inhibitory concentration (MIC) by more than a factor of 2.
161
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
162
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
163
package insert for CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) 5% and
164
10% Oral Suspension.
165
Aerobic gram-positive microorganisms
166
Enterococcus faecalis (Many strains are only moderately susceptible.)
167
Staphylococcus aureus (methicillin-susceptible strains only)
168
Staphylococcus epidermidis (methicillin-susceptible strains only)
169
Staphylococcus saprophyticus
170
Streptococcus pneumoniae (penicillin-susceptible strains only)
171
Streptococcus pyogenes
172
Aerobic gram-negative microorganisms
173
Campylobacter jejuni
Proteus mirabilis
174
Citrobacter diversus
Proteus vulgaris
175
Citrobacter freundii
Providencia rettgeri
176
Enterobacter cloacae
Providencia stuartii
177
Escherichia coli
Pseudomonas aeruginosa
178
Haemophilus influenzae
Salmonella typhi
179
Haemophilus parainfluenzae
Serratia marcescens
180
Klebsiella pneumoniae
Shigella boydii
181
Moraxella catarrhalis
Shigella dysenteriae
182
Morganella morganii
Shigella flexneri
183
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Neisseria gonorrhoeae
Shigella sonnei
184
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
185
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
186
ANTHRAX – ADDITIONAL INFORMATION).
187
The following in vitro data are available, but their clinical significance is unknown.
188
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
189
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
190
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
191
adequate and well-controlled clinical trials.
192
Aerobic gram-positive microorganisms
193
Staphylococcus haemolyticus
194
Staphylococcus hominis
195
Streptococcus pneumoniae (penicillin-resistant strains only)
196
Aerobic gram-negative microorganisms
197
Acinetobacter Iwoffi
Pasteurella multocida
198
Aeromonas hydrophila
Salmonella enteritidis
199
Edwardsiella tarda
Vibrio cholerae
200
Enterobacter aerogenes
Vibrio parahaemolyticus
201
Klebsiella oxytoca
Vibrio vulnificus
202
Legionella pneumophila
Yersinia enterocolitica
203
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
204
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium
205
difficile.
206
Susceptibility Tests
207
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
208
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
209
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
210
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum
211
concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be
212
interpreted according to the following criteria:
213
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae,
214
and Neisseria gonorrhoeaea:
215
MIC (µg/mL)
Interpretation
216
≤ 1
Susceptible
(S)
217
2
Intermediate
(I)
218
≥ 4
Resistant
(R)
219
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
220
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
221
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
222
MIC (µg/mL)
Interpretation
223
≤ 1
Susceptible
(S)
224
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
225
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
226
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The current absence of data on resistant strains precludes defining any results other than
227
“Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be
228
submitted to a reference laboratory for further testing.
229
For testing Neisseria gonorrhoeaec:
230
MIC (µg/mL)
Interpretation
231
≤ 0.06
Susceptible
(S)
232
0.12 – 0.5
Intermediate
(I)
233
≥ 1
Resistant
(R)
234
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
235
growth supplement.
236
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
237
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
238
indicates that the result should be considered equivocal, and, if the microorganism is not fully
239
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
240
possible clinical applicability in body sites where the drug is physiologically concentrated or in
241
situations where high dosage of drug can be used. This category also provides a buffer zone, which
242
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
243
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
244
compound in the blood reaches the concentrations usually achievable; other therapy should be
245
selected.
246
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
247
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
248
provide the following MIC values:
249
Organism
MIC (µg/mL)
250
E. faecalis
ATCC 29212
0.25 – 2.0
251
E. coli
ATCC 25922
0.004 – 0.015
252
H. influenzaea
ATCC 49247
0.004 – 0.03
253
N. gonorrhoeaeb
ATCC 49226
0.001 – 0.008
254
P. aeruginosa
ATCC 27853
0.25 – 1.0
255
S. aureus
ATCC 29213
0.12 – 0.5
256
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
257
microdilution procedure using Haemophilus Test Medium (HTM)1.
258
bThis quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar
259
dilution procedure using GC agar base and 1% defined growth supplement.
260
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
261
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
262
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure
263
uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
264
ciprofloxacin.
265
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
266
ciprofloxacin disk should be interpreted according to the following criteria:
267
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae,
268
and Neisseria gonorrhoeaea:
269
Zone Diameter (mm)
Interpretation
270
≥ 21
Susceptible
(S)
271
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 – 20
Intermediate
(I)
272
≤ 15
Resistant
(R)
273
aThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-
274
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
275
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
276
Zone Diameter (mm)
Interpretation
277
≥ 21
Susceptible
(S)
278
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
279
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
280
The current absence of data on resistant strains precludes defining any results other than
281
“Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should
282
be submitted to a reference laboratory for further testing.
283
For testing Neisseria gonorrhoeaec:
284
Zone Diameter (mm)
Interpretation
285
≥ 41
Susceptible
(S)
286
28 – 40
Intermediate
(I)
287
≤ 27
Resistant
(R)
288
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1%
289
defined growth supplement.
290
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
291
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
292
As with standardized dilution techniques, diffusion methods require the use of laboratory control
293
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
294
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
295
laboratory test quality control strains:
296
Organism
Zone Diameter (mm)
297
E. coli
ATCC 25922
30 – 40
298
H. influenzaea
ATCC 49247
34 – 42
299
N. gonorrhoeaeb
ATCC 49226
48 – 58
300
P. aeruginosa
ATCC 27853
25 – 33
301
S. aureus
ATCC 25923
22 – 30
302
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
303
Haemophilus Test Medium (HTM)2.
304
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC
305
49226 performed by disk diffusion using GC agar base and 1% defined growth supplement.
306
INDICATIONS AND USAGE
307
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
308
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
309
ADMINISTRATION for specific recommendations.
310
311
Adult Patients:
312
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae,
313
Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter
314
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diversus,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
Staphylococcus
epidermidis,
315
Staphylococcus saprophyticus, or Enterococcus faecalis.
316
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
317
saprophyticus.
318
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
319
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
320
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
321
Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the
322
treatment of acute exacerbations of chronic bronchitis.
323
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment
324
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
325
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
326
catarrhalis.
327
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
328
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
329
morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-
330
susceptible), Staphylococcus epidermidis, or Streptococcus pyogenes.
331
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
332
aeruginosa.
333
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
334
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
335
fragilis.
336
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
337
Shigella boydii†, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial therapy
338
is indicated.
339
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
340
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not
341
been demonstrated.
342
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
343
344
Pediatric patients (1 to 17 years of age):
345
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
346
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
347
population due to an increased incidence of adverse events compared to controls, including events
348
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
349
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones,
350
is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile
351
animals. (See ANIMAL PHARMACOLOGY.)
352
353
Adult and Pediatric Patients:
354
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
355
exposure to aerosolized Bacillus anthracis.
356
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably
357
likely to predict clinical benefit and provide the basis for this indication.4 (See also,
358
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).
359
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
360
significant outcome, efficacy was studied in fewer than 10 patients.
361
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
362
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
363
administered. Appropriate culture and susceptibility tests should be performed before treatment in
364
order to isolate and identify organisms causing infection and to determine their susceptibility to
365
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
366
results become available appropriate therapy should be continued. As with other drugs, some strains
367
of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with
368
ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide
369
information not only on the therapeutic effect of the antimicrobial agent but also on the possible
370
emergence of bacterial resistance.
371
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
372
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
373
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to
374
be caused by susceptible bacteria. When culture and susceptibility information are available, they
375
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
376
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
377
CONTRAINDICATIONS
378
CIPRO (ciprofloxacin hydrochloride) is contraindicated in persons with a history of hypersensitivity
379
to ciprofloxacin or any member of the quinolone class of antimicrobial agents.
380
WARNINGS
381
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
382
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
383
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
384
385
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
386
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
387
events compared to controls, including events related to joints and/or surrounding tissues, has been
388
observed. (See ADVERSE REACTIONS.)
389
390
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
391
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions
392
of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing
393
joints and other signs of arthropathy in immature animals of various species. (See ANIMAL
394
PHARMACOLOGY.)
395
396
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
397
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
398
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
399
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
400
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
401
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
402
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
403
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
404
risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
405
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
406
and ADVERSE REACTIONS.)
407
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
408
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND
409
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
410
respiratory failure. Although similar serious adverse effects have been reported in patients receiving
411
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
412
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored
413
and dosage adjustments made as appropriate.
414
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
415
some following the first dose, have been reported in patients receiving quinolone therapy. Some
416
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
417
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
418
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine.
419
Oxygen, intravenous steroids, and airway management, including intubation, should be administered
420
as indicated.
421
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
422
necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along
423
with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded.
424
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of
425
hypersensitivity.
426
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
427
antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-
428
threatening. Therefore, it is important to consider this diagnosis in patients who present with
429
diarrhea subsequent to the administration of antibacterial agents.
430
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
431
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
432
“antibiotic-associated colitis.”
433
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
434
initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In
435
moderate to severe cases, consideration should be given to management with fluids and electrolytes,
436
protein supplementation, and treatment with an antibacterial drug clinically effective against C.
437
difficile colitis. Drugs that inhibit peristalsis should be avoided.
438
Tendon Rupture: Ruptures of the shoulder, hand, and Achilles and other tendon ruptures that
439
required surgical repair or resulted in prolonged disability have been reported in patients receiving
440
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that the risk may be
441
increased in patients receiving concomitant corticosteroids, especially in the elderly. Ciprofloxacin
442
should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.
443
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
444
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
445
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
446
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis
447
after three months.
448
PRECAUTIONS
449
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
450
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
451
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
452
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
453
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
454
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
455
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
456
(See WARNINGS, Information for Patients, and Drug Interactions.)
457
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of
458
renal function. (See DOSAGE AND ADMINISTRATION.)
459
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
460
been observed in patients who are exposed to direct sunlight while receiving some members of the
461
quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if
462
phototoxicity occurs.
463
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
464
hematopoietic function, is advisable during prolonged therapy.
465
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
466
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient
467
and increases the risk of the development of drug-resistant bacteria.
468
Information for Patients:
469
Patients should be advised:
470
• that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
471
to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
472
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
473
told that although it is common to feel better early in the course of therapy, the medication should
474
be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
475
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
476
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
477
other antibacterial drugs in the future.
478
• that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
479
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
480
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, or with other
481
products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours
482
before or six hours after taking these products. Ciprofloxacin should not be taken with dairy
483
products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin
484
may be significantly reduced; however, ciprofloxacin may be taken with a meal that contains these
485
products.
486
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
487
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
488
• to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to
489
discontinue therapy if phototoxicity occurs.
490
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they
491
experience pain, inflammation, or rupture of a tendon.
492
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
493
they react to this drug before they operate an automobile or machinery or engage in activities
494
requiring mental alertness or coordination.
495
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
496
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
497
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
498
notify their physician before taking this drug if there is a history of this condition.
499
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
500
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
501
should inform their child’s physician if the child has a history of joint-related problems before
502
taking this drug. Parents of pediatric patients should also notify their child’s physician of any joint-
503
related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
504
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
505
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
506
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
507
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
508
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
509
monitored and dosage adjustments made as appropriate.
510
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
511
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
512
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
513
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
514
tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease
515
its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE
516
AND ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.)
517
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
518
ciprofloxacin.
519
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
520
concomitant ciprofloxacin.
521
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare
522
occasions, resulted in severe hypoglycemia.
523
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
524
creatinine in patients receiving cyclosporine concomitantly.
525
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
526
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
527
prothrombin time or other suitable coagulation tests should be closely monitored.
528
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the
529
level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
530
concomitantly.
531
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
532
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
533
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
534
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
535
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time
536
to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
537
ciprofloxacin.
538
Animal studies have shown that the combination of very high doses of quinolones and certain non-
539
steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.
540
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
541
conducted with ciprofloxacin, and the test results are listed below:
542
Salmonella/Microsome Test (Negative)
543
E. coli DNA Repair Assay (Negative)
544
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
545
Chinese Hamster V79 Cell HGPRT Test (Negative)
546
Syrian Hamster Embryo Cell Transformation Assay (Negative)
547
Saccharomyces cerevisiae Point Mutation Assay (Negative)
548
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
549
Rat Hepatocyte DNA Repair Assay (Positive)
550
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
551
results:
552
Rat Hepatocyte DNA Repair Assay
553
Micronucleus Test (Mice)
554
Dominant Lethal Test (Mice)
555
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
556
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
557
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
558
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
559
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
560
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
561
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
562
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to
563
maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
564
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
565
weeks in mice treated concomitantly with UVA and other quinolones.3
566
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There
567
are no data from similar models using pigmented mice and/or fully haired mice. The clinical
568
significance of these findings to humans is unknown.
569
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-
570
times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
571
impairment.
572
Pregnancy: Teratogenic Effects. Pregnancy Category C:
573
There are no adequate and well-controlled studies in pregnant women. An expert review of published
574
data on experiences with ciprofloxacin use during pregnancy by TERIS – the Teratogen Information
575
System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial
576
teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no
577
risk.7
578
A controlled prospective observational study followed 200 women exposed to fluoroquinolones
579
(52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero
580
exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major
581
malformations. The reported rates of major congenital malformations were 2.2% for the
582
fluoroquinolone group and 2.6% for the control group (background incidence of major malformations
583
is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the
584
groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in
585
the ciprofloxacin exposed children.
586
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure
587
(93% first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester.
588
The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones
589
overall were both within background incidence ranges. No specific patterns of congenital
590
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
abnormalities were found. The study did not reveal any clear adverse reactions due to in utero
591
exposure to ciprofloxacin.
592
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
593
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
594
studies, of which most experience is from short term, first trimester exposure, are insufficient to
595
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
596
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
597
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
598
(see WARNINGS).
599
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
600
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
601
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose
602
levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic
603
dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an
604
increased incidence of abortion, but no teratogenicity was observed at either dose level. After
605
intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
606
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no
607
embryotoxicity or teratogenicity was observed. (See WARNINGS.)
608
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed
609
by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants
610
nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing
611
or to discontinue the drug, taking into account the importance of the drug to the mother.
612
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
613
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
614
PHARMACOLOGY.)
615
Inhalational Anthrax (Post-Exposure)
616
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-
617
benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
618
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE
619
AND
ADMINISTRATION
and
INHALATIONAL
ANTHRAX
–
ADDITIONAL
620
INFORMATION.
621
622
Complicated Urinary Tract Infection and Pyelonephritis
623
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
624
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice
625
in the pediatric population due to an increased incidence of adverse events compared to the controls,
626
including events related to joints and/or surrounding tissues. The rates of these events in pediatric
627
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up
628
were 9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at
629
any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate
630
of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the
631
ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS
632
and CLINICAL STUDIES.)
633
Cystic Fibrosis
634
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
635
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
636
fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
637
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
638
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
639
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
640
monitoring in the study included periodic range of motion examinations and gait assessments by
641
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
642
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
643
of repeated exposure to ciprofloxacin.
644
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
645
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
646
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
647
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
648
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
649
patients developed arthritis of the knee nine days after a ten day course of treatment with
650
ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other
651
abnormalities eight months after treatment. However, the relationship of this event to the patient’s
652
course of ciprofloxacin can not be definitively determined, particularly since patients with cystic
653
fibrosis may develop arthralgias/arthritis as part of their underlying disease process.
654
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
655
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater
656
than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall
657
differences in safety or effectiveness were observed between these subjects and younger subjects, and
658
other reported clinical experience has not identified differences in responses between the elderly and
659
younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled
660
out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
661
reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary
662
for patients greater than 65 years of age with normal renal function. However, since some older
663
individuals experience reduced renal function by virtue of their advanced age, care should be taken in
664
dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See
665
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
666
ADVERSE REACTIONS
667
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
668
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
669
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
670
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.0% of orally
671
treated patients.
672
The most frequently reported drug related events, from clinical trials of all formulations, all dosages,
673
all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
674
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
675
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are
676
listed below.
677
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities,
678
injection site reaction (ciprofloxacin intravenous)
679
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
680
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis, phlebitis,
681
tachycardia, migraine, hypotension
682
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
683
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
684
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia,
685
abnormal gait, grand mal convulsion
686
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
687
gastrointestinal bleeding, cholestatic jaundice, hepatitis
688
HEMIC/LYMPHATIC: lymphadenopathy, petechia
689
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
690
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare
691
up of gout
692
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention,
693
urethral bleeding, vaginitis, acidosis, breast pain
694
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis,
695
bronchospasm, pulmonary embolism
696
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity, flushing,
697
fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous
698
candidiasis, hyperpigmentation, erythema nodosum, sweating
699
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness
700
of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste,
701
chromatopsia
702
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators
703
to be related to elevated serum levels of theophylline possibly as a result of drug interaction with
704
ciprofloxacin.
705
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
706
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
707
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
708
control drugs.
709
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
710
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
711
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was
712
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
713
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
714
days). The primary objective of the study was to assess musculoskeletal and neurological safety
715
within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
716
comparator-treated patients enrolled.
717
718
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
719
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-
720
emergent). These events were evaluated in a comprehensive fashion and included such conditions as
721
arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain,
722
pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee,
723
elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events
724
were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in comparator-treated
725
patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events
726
occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of
727
end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events.
728
The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless
729
of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were more likely to
730
report more than one event and on more than one occasion compared to control patients. These events
731
occurred in all age groups and the rates were consistently higher in the ciprofloxacin group compared
732
to the control group. At the end of 1 year, the rate of these events reported at any time during that
733
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-
734
treated patients.
735
736
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
737
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
738
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
739
excluded. The patient recovered by 4 months without surgical intervention.
740
741
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
742
743
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
744
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that
745
of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
746
interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the control
747
group.
748
749
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in
750
the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness,
751
nervousness, insomnia, and somnolence.
752
753
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
754
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
755
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
756
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
757
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
758
Discontinuation of drug due to an adverse events were observed in 3% (10/335) of ciprofloxacin-
759
treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at
760
least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%,
761
accidental injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and
762
rash 1.8%.
763
764
In addition to the events reported in pediatric patients in clinical trials, it should be expected that
765
events reported in adults during clinical trials or post-marketing experience may also occur in
766
pediatric patients.
767
768
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
769
marketing experience with quinolones, including ciprofloxacin. Because these events are reported
770
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
771
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
772
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
773
frequency of the reporting, or (3) strength of causal connection to the drug.
774
Agitation, agranulocytosis, albuminuria, anaphylactic reactions, anosmia, candiduria, cholesterol
775
elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme,
776
exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
777
failure, hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
778
marrow depression (life threatening), methemoglobinemia, monoliasis (oral, gastrointestinal, vaginal)
779
myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
780
pancytopenia (life threatening or fatal outcome), phenytoin alteration (serum), potassium elevation
781
(serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
782
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis
783
(toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis,
784
tendon rupture, toxic epidermal necrolysis, triglyceride elevation (serum), twitching, vaginal
785
candidiasis, and vasculitis. (See PRECAUTIONS.)
786
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
787
regard to drug relationship are listed below:
788
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
789
(0.8%), LDH (0.4%), serum bilirubin (0.3%).
790
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated
791
blood platelets (0.1%), pancytopenia (0.1%).
792
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
793
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
794
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
795
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
796
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
797
OVERDOSAGE
798
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
799
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
800
observed and given supportive treatment, including monitoring of renal function and administration of
801
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
802
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
803
is removed from the body after hemodialysis or peritoneal dialysis.
804
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice,
805
rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest
806
oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical
807
signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs.
808
In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was
809
delayed in these animals, occurring 10-14 days after dosing.
810
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
811
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
812
DOSAGE AND ADMINISTRATION - ADULTS
813
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the
814
Dosage Guidelines table.
815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The determination of dosage for any particular patient must take into consideration the severity and
816
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s host-
817
defense mechanisms, and the status of renal function and hepatic function.
818
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
819
however, for severe and complicated infections more prolonged therapy may be required.
820
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
821
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
822
solution, or other products containing calcium, iron or zinc.
823
824
ADULT DOSAGE GUIDELINES
825
Infection
Severity
Dose
Frequency Usual Durations†
826
Urinary Tract
Acute Uncomplicated
100 mg or 250 mg
q 12 h
3 Days
827
Mild/Moderate
250 mg
q 12 h
7 to 14 Days
828
Severe/Complicated
500 mg
q 12 h
7 to 14 Days
829
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 Days
830
Prostatitis
831
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
832
Severe/Complicated
750 mg
q 12 h
7 to 14 days
833
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
834
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 Days
835
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 Days
836
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
837
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
838
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 Days
839
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 Days
840
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 Days
841
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
842
Gonococcal Infections
843
Inhalational anthrax
500 mg
q 12 h
60 Days
844
(post-exposure)**
845
846
847
* used in conjunction with metronidazole
848
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have
849
disappeared, except for inhalational anthrax (post-exposure).
850
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
851
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
852
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various
853
human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
854
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
855
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of
856
the physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing
857
regimens).
858
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Equivalent AUC Dosing Regimens
859
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
860
250 mg Tablet q 12 h
200 mg I.V. q 12 h
861
500 mg Tablet q 12 h
400 mg I.V. q 12 h
862
750 mg Tablet q 12 h
400 mg I.V. q 8 h
863
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
864
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
865
through the intestine. These alternative pathways of drug elimination appear to compensate for the
866
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage
867
is recommended, particularly for patients with severe renal dysfunction. The following table provides
868
dosage guidelines for use in patients with renal impairment:
869
RECOMMENDED STARTING AND MAINTENANCE DOSES
870
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
871
Creatinine Clearance (mL/min)
Dose
872
> 50
See Usual Dosage.
873
30 – 50
250 – 500 mg q 12 h
874
5 – 29
250 – 500 mg q 18 h
875
Patients on hemodialysis
250–500 mg q 24 h (after dialysis)
876
or Peritoneal dialysis)
877
When only the serum creatinine concentration is known, the following formula may be used to
878
estimate creatinine clearance.
879
Men: Creatinine clearance (mL/min) = Weight (kg) x (140 - age)
880
72 x serum creatinine (mg/dL)
881
Women: 0.85 x the value calculated for men.
882
The serum creatinine should represent a steady state of renal function.
883
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be
884
administered at the intervals noted above. Patients should be carefully monitored.
885
DOSAGE AND ADMINISTRATION - PEDIATRICS
886
887
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
888
Guidelines table. An increased incidence of adverse events compared to controls, including events
889
related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS and
890
CLINICAL STUDIES.)
891
892
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
893
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
894
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
895
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
896
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
897
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 8 hours
Complicated
Urinary Tract or
Pyelonephritis
(patients from 1
to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 12
hours
10-21
days*
Intravenous
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was
898
determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
899
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
900
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved
901
in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations
902
in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
903
904
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
905
complicated urinary tract infection and pyelonephritis. No information is available on dosing
906
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e.,
907
creatinine clearance of < 50 mL/min/1.73m2).
908
909
HOW SUPPLIED
910
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
911
tablets containing 100 mg or 250 mg ciprofloxacin. The 100 mg tablet is coded with the word
912
“CIPRO” on one side and “100” on the reverse side. The 250 mg tablet is coded with the word
913
“CIPRO” on one side and “250” on the reverse side. CIPRO is also available as capsule shaped,
914
slightly yellowish film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet
915
is coded with the word “CIPRO” on one side and “500” on the reverse side. The 750 mg tablet is
916
coded with the word “CIPRO” on one side and “750” on the reverse side. CIPRO 250 mg, 500 mg,
917
and 750 mg are available in bottles of 50, 100, and Unit Dose packages of 100. The 100 mg strength is
918
available only as CIPRO Cystitis pack containing 6 tablets for use only in female patients with acute
919
uncomplicated cystitis.
920
Strength
NDC Code
Tablet Identification
921
Bottles of 50:
750 mg
NDC 0026-8514-50
CIPRO 750
922
Bottles of 100:
250 mg
NDC 0026-8512-51
CIPRO 250
923
500 mg
NDC 0026-8513-51
CIPRO 500
924
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Unit Dose
925
Package of 100:
250 mg
NDC 0026-8512-48
CIPRO 250
926
500 mg
NDC 0026-8513-48
CIPRO 500
927
750 mg
NDC 0026-8514-48
CIPRO 750
928
Cystitis
929
Package of 6:
100 mg
NDC 0026-8511-06
CIPRO 100
930
Store below 30°C (86°F).
931
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
932
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
933
pharmacist. See Instructions To The Pharmacist For Use/Handling.
934
Total volume
Ciprofloxacin
Ciprofloxacin
935
Strengths
after reconstitution
Concentration
contents per bottle
NDC Code
936
5%
100 mL
250 mg/5 mL
5,000 mg
0026-8551-36
937
10%
100 mL
500 mg/5 mL
10,000 mg
0026-8553-36
938
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
939
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
940
teaspoon is provided for the patient.
941
ANIMAL PHARMACOLOGY
942
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
943
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
944
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
945
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
946
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
947
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
948
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
949
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
950
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
951
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
952
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
953
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
954
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
955
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human
956
urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single
957
oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose
958
based upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological
959
changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same
960
duration (approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
961
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
962
hypotensive effects. These effects are considered to be related to histamine release, since they are
963
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
964
produces hypotension but the effect in this species is inconsistent and less pronounced.
965
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
966
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
967
quinolones.
968
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
969
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL STUDIES
970
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
971
972
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
973
population due to an increased incidence of adverse events compared to controls, including events
974
related to joints and/or surrounding tissues.
975
Ciprofloxacin, administered I.V. and /or orally, was compared to a cephalosporin for treatment of
976
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of
977
age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa
978
Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration
979
of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to
980
assess musculoskeletal and neurological safety.
981
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
982
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
983
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline,
984
no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
985
986
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
987
between ciprofloxacin and the comparator group as shown below.
988
989
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
990
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic
Eradication
of
the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
991
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or
992
new infections.
993
994
INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
995
INFORMATION
996
The mean serum concentrations of ciprofloxacin associated with a statistically significant
997
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
998
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
999
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
1000
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
1001
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
1002
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
1003
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
1004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
1005
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
1006
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
1007
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
1008
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
1009
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
1010
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
1011
provide the basis for this indication.4
1012
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
1013
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
1014
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
1015
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-
1016
dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough
1017
concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for
1018
animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
1019
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-
1020
treated animal that died of anthrax did so following the 30-day drug administration period.6
1021
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
1022
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
1023
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
1024
which must be combined prior to dispensing.
1025
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
1026
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of ciprofloxacin.
1027
Appropriate Dosing Volumes of the Oral Suspensions:
1028
Dose
5%
10%
1029
250 mg
5 mL
2.5 mL
1030
500 mg
10 mL
5 mL
1031
750 mg
15 mL
7.5 mL
1032
Preparation of the suspension:
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1. The small bottle
contains the
microcapsules, the
large bottle contains
the diluent.
3. Pour the
microcapsules
completely into the
larger bottle of
diluent. Do not add
water to the
suspension.
2. Open both bottles.
Child-proof cap: Press
down according to
instructions on the cap
while turning to the left.
4. Remove the top layer of
the diluent bottle label
(to reveal the CIPRO
Oral Suspension label).
Close the large bottle
completely according to
the directions on the cap
and shake vigorously for
about 15 seconds. The
suspension is ready for
use.
1.
2.
3.
4.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Oral Suspension should not be administered through feeding tubes due to its physical
1047
characteristics.
1048
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
1049
approximately 15 seconds and not to chew the microcapsules.
1050
1051
References:
1052
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
1053
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
1054
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
1055
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests-
1056
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
1057
PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
1058
Product’s Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from
1059
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
1060
Rockville, MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs
1061
for Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline,
1062
and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. 6.
1063
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
1064
Dis 1993; 167:1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for
1065
clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
1066
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
1067
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1068
1998;42(6):1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after
1069
prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology
1070
information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
1071
1072
Patient Information About:
1073
CIPRO®
1074
(ciprofloxacin hydrochloride) TABLETS
1075
CIPRO®
1076
(ciprofloxacin*) ORAL SUSPENSION
1077
This section contains important patient information about CIPRO (ciprofloxacin hydrochloride)
1078
Tablets and CIPRO (ciprofloxacin*) Oral Suspension and should be read completely before you begin
1079
treatment. This section does not take the place of discussion with your doctor or health care
1080
professional about your medical condition or your treatment. This section does not list all benefits and
1081
risks of CIPRO. If you have any concerns about your condition or your medicine, ask your doctor.
1082
Only your doctor can determine if CIPRO is right for you.
1083
What is CIPRO?
1084
CIPRO is an antibiotic used to treat bladder, kidney, prostate, cervix, stomach, intestine, lung, sinus,
1085
bone, and skin infections caused by certain germs called bacteria. CIPRO kills many types of bacteria
1086
that can infect these areas of the body. CIPRO has been shown in a large number of clinical trials to
1087
be safe and effective for the treatment of bacterial infections.
1088
Sometimes viruses rather than bacteria may infect the lungs and sinuses (for example the common
1089
cold). CIPRO, like all other antibiotics, does not kill viruses. You should contact your doctor if your
1090
condition is not improving while taking CIPRO.
1091
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO Tablets are white to slightly yellow in color and are available in 100 mg, 250 mg, 500 mg and
1092
750 mg strengths. CIPRO Oral Suspension is white to slightly yellow in color and is available in
1093
concentrations of 250 mg per teaspoon (5%) and 500 mg per teaspoon (10%).
1094
How and when should I take CIPRO?
1095
CIPRO Tablets:
1096
Unless directed otherwise by your physician, CIPRO should be taken twice a day at approximately the
1097
same time, in the morning and in the evening. CIPRO can be taken with food or on an empty stomach.
1098
CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone;
1099
however, CIPRO may be taken with a meal that contains these products.
1100
You should take CIPRO for as long as your doctor prescribes it, even after you start to feel better.
1101
Stopping an antibiotic too early may result in failure to cure your infection. Do not take a double dose
1102
of CIPRO even if you miss a dose by mistake.
1103
CIPRO Oral Suspension:
1104
Take CIPRO Oral Suspension in the same way as above. In addition, remember to shake the bottle
1105
vigorously each time before use for approximately 15 seconds to make sure the suspension is
1106
mixed well. Be sure to swallow the required amount of suspension. Do not chew the microcapsules.
1107
Close the bottle completely after use. The product can be used for 14 days when stored in a
1108
refrigerator or at room temperature. After treatment has been completed, any remaining suspension
1109
should be discarded.
1110
Who should not take CIPRO?
1111
You should not take CIPRO if you have ever had a severe reaction to any of the group of antibiotics
1112
known as “quinolones”.
1113
CIPRO is not recommended during pregnancy or nursing, as the effects of CIPRO on the unborn child
1114
or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking CIPRO
1115
talk to your doctor before taking this medication.
1116
Due to possible side effects, CIPRO is not recommended for persons less than 18 years of age except
1117
for specific serious infections, such as complicated urinary tract infections.
1118
What are the possible side effects of CIPRO?
1119
CIPRO is generally well tolerated. The most common side effects, which are usually mild, include
1120
nausea, diarrhea, vomiting, and abdominal pain/discomfort. If diarrhea persists, call your health care
1121
professional.
1122
Rare cases of allergic reactions have been reported in patients receiving quinolones, including CIPRO,
1123
even after just one dose. If you develop hives, difficulty breathing, or other symptoms of a severe
1124
allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should stop
1125
taking CIPRO and call your health care professional.
1126
Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light
1127
such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet
1128
light while you are taking CIPRO.
1129
You should be careful about driving or operating machinery until you are sure CIPRO is not causing
1130
dizziness. Convulsions have been reported in patients receiving quinolone antibiotics including
1131
ciprofloxacin. Be sure to let your physician know if you have a history of convulsions. Quinolones,
1132
including ciprofloxacin, have been rarely associated with other central nervous system events
1133
including confusion, tremors, hallucinations, and depression.
1134
CIPRO has been rarely associated with inflammation of tendons. If you experience pain, swelling or
1135
rupture of a tendon, you should stop taking CIPRO and call your health care professional.
1136
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO has been associated with an increased rate of side effects with joints and surrounding
1137
structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their
1138
child’s physician if the child has a history of joint-related problems before taking this drug. Parents of
1139
pediatric patients should also notify their child’s physician of any joint related problems that occur
1140
during or following CIPRO therapy.
1141
If you notice any side effects not mentioned in this section, or if you have any concerns about side
1142
effects you may be experiencing, please inform your health care professional.
1143
What about other medications I am taking?
1144
CIPRO can affect how other medicines work. Tell your doctor about all other prescription and non-
1145
prescription medicines or supplements you are taking. This is especially important if you are taking
1146
theophylline. Other medications including warfarin, glyburide, and phenytoin may also interact with
1147
CIPRO.
1148
Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium,
1149
aluminum, iron or zinc can interfere with the absorption of CIPRO and may prevent it from working.
1150
Other medications such as sulcrafate and Videx® (didanosine) chewable/buffered tablets or pediatric
1151
powder may also stop CIPRO from working. You should take CIPRO either 2 hours before or 6 hours
1152
after taking these products.
1153
What if I have been prescribed CIPRO for possible anthrax exposure?
1154
CIPRO has been approved to reduce the chance of developing anthrax infection following exposure to
1155
the anthrax bacteria. In general, CIPRO is not recommended for children; however, it is approved for
1156
use in patients younger than 18 years old for anthrax exposure. If you are pregnant, or plan to become
1157
pregnant while taking CIPRO, you and your doctor should discuss if the benefits of taking CIPRO for
1158
anthrax outweigh the risks.
1159
CIPRO is generally well tolerated. Side effects that may occur during treatment to prevent anthrax
1160
might be acceptable due to the seriousness of the disease. You and your doctor should discuss the
1161
risks of not taking your medicine against the risks of experiencing side effects.
1162
CIPRO can cause dizziness, confusion, or other similar side effects in some people. Therefore, it is
1163
important to know how CIPRO affects you before driving a car or performing other activities that
1164
require you to be alert and coordinated such as operating machinery.
1165
Your doctor has prescribed CIPRO only for you. Do not give it to other people. Do not use it for a
1166
condition for which it was not prescribed. You should take your CIPRO for as long as your doctor
1167
prescribes it; stopping CIPRO too early may result in failure to prevent anthrax.
1168
Remember:
1169
Do not give CIPRO to anyone other than the person for whom it was prescribed.
1170
Take your dose of CIPRO in the morning and in the evening.
1171
Complete the course of CIPRO even if you are feeling better.
1172
Keep CIPRO and all medications out of reach of children.
1173
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
1174
1175
1176
1177
Bayer Pharmaceuticals Corporation
1178
400 Morgan Lane
1179
West Haven, CT 06516
1180
1181
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx Only
1182
1183
xxxxxxx
3/04
Bay o 9867
5202-2-A-U.S.-14
xxxxx
1184
©2004 Bayer Pharmaceuticals CorporationPrinted in U.S.A.
1185
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy.
1186
CIPRO (ciprofloxacin HCl) Tablets Made in U.S.A. and Germany
1187
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
XXXXXXXXX
3/25/04
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other
antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
DESCRIPTION
CIPRO® I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.) administration.
Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N)
hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V. solutions are available as sterile 1.0%
aqueous concentrates, which are intended for dilution prior to administration, and as 0.2% ready-for-use infusion
solutions in 5% Dextrose Injection. All formulas contain lactic acid as a solubilizing agent and hydrochloric acid for
pH adjustment. The pH range for the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2%
ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride. Solutions in
contact with the plastic container can leach out certain of its chemical components in very small amounts within the
expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has
been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue
culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean
maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the concentrations at 12 hours
were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (mg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously.
Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no
evidence of drug accumulation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by first pass
metabolism. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours has been shown
to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral
dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours
has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every
12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200
mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given
every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin
blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat,
muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are
generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of
the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which together
account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr. After
intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug.
Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL 0–2 hours after dosing and are
generally greater than 15 µg/mL 8–12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations
generally exceed 400 µg/mL 0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing.
The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours
after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous
dosing, only a small amount of the administered dose (<1%) is recovered from the bile as unchanged drug.
Approximately 15% of an I.V. dose is recovered from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin
indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
adults. Although the Cmax is increased 16–40%, the increase in mean AUC is approximately 30%, and can be at
least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%)
prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric
Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage adjustments
may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin
pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients with acute hepatic
insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7
years, the mean Cmax was 2.4 mg/L (range: 1.5 – 3.4 mg/L) and the mean AUC was 9.2 mg*h/L (range: 5.8 – 14.9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mg*h/L). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing
(10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 mg/L (range: 4.6 – 8.3 mg/L) in 10 children less than 1 year of age; and 7.2 mg/L
(range: 4.7 – 11.8 mg/L) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range:
11.8 – 32.0 mg*h/L) and 16.5 mg*h/L (range: 11.0 – 23.8 mg*h/L) in the respective age groups. These values are
within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of
pediatric patients with various infections, the predicted mean half-life in children is approximately 4 - 5 hours, and
the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin and
theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and
piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II
(DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and
recombination. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to
these classes of drugs may be susceptible to ciprofloxacin and other quinolones. There is no known cross-
resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops
slowly by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro.
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC)
by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in
clinical infections as described in the INDICATIONS AND USAGE section of the package insert for CIPRO I.V.
(ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a
surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX - ADDITIONAL
INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥90%)
strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin intravenous
formulations in treating clinical infections due to these microorganisms have not been established in adequate and
well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
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Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should
be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin
powder. The MIC values should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using
cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae
and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains
yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for
further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the
blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be
considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the
test should be repeated. This category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a
buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the
blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the
technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC
values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25
– 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25
– 1.0
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S. aureus
ATCC 29213
0.12
– 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized
procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks
impregnated with 5-mg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mg ciprofloxacin
disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar
supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains
yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference
laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of
the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms
that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg
ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test
Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous administration offers a
route of administration advantageous to the patient. Please see DOSAGE AND ADMINISTRATION for specific
recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia), Klebsiella
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus
epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus
parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute exacerbations
of chronic bronchitis.
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NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of presumed or
confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter
freundii, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis,
or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by Escherichia coli,
Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See CLINICAL
STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to
an increased incidence of adverse events compared to controls, including events related to joints and/or
surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL
STUDIES.) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes
in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to
aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication.4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify
organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with CIPRO I.V. may be
initiated before results of these tests are known; once results become available, appropriate therapy should be
continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during
treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide
information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of
bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other
antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to ciprofloxacin or any
member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND
LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing
Mothers subsections.)
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Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in
the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological
examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related
quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in
immature animals of various species. (See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous
system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal
thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones,
ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose
to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of
other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal
dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING
CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These
reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious
adverse events have been reported in patients receiving theophylline alone, the possibility that these reactions may
be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of
theophylline should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea,
urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions
require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen,
intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as
clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with
fatal outcome have also been reported extremely rarely in patients receiving ciprofloxacin along with other drugs.
The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be
discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea subsequent to the administration
of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia.
Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.
Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and
treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should
be avoided.
Tendon Rupture: Ruptures of the shoulder, hand, and Achilles and other tendon ruptures that required surgical
repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ciprofloxacin.
Post-marketing surveillance reports indicate that the risk may be increased in patients receiving concomitant
corticosteroids, especially in the elderly. Ciprofloxacin should be discontinued if the patient experiences pain,
inflammation, or rupture of a tendon.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW INFUSION OVER A
PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the intravenous administration of
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ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small veins of the hand
are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS,
Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine
of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to
ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine
should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of
highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal function.
(See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been
observed in some patients who were exposed to direct sunlight while receiving some members of the quinolone
class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant
bacteria.
Information For Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO IV should only be used to treat bacterial infections. They do not treat viral
infections (e.g., the common cold). When CIPRO IV is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be taken exactly
as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the
immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable
by CIPRO IV or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to
discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to
this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or
coordination.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of caffeine
accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience pain,
inflammation, or rupture of a tendon.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to notify their
physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding
tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their child’s
physician if the child has a history of joint-related problems before taking this drug. Parents of pediatric patients
should also notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin
therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may
lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in
increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided,
serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This
may lead to reduced clearance of caffeine and prolongation of its serum half-life.
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Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in
patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant
ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients, resulted in
severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given
concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or
its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation
tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of
ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially
leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic
reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant
ciprofloxacin therapy is indicated.
Metoclopramide accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma
concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Animal studies have shown that the combination of very high doses of quinolones and certain non-steroidal anti-
inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V. piperacillin
sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2 hour and 1.18 µg/mL
between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been conducted
with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to
ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7-
and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of
UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5
hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time
to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin
(mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34
weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from
16–32 weeks in mice treated concomitantly with UVA and other quinolones.3
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In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from
similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans
is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the
highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies in
pregnant women. An expert review of published data on experiences with ciprofloxacin use during pregnancy by
TERIS – the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there
is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to
ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluoroquinolones during
embryogenesis was not associated with increased risk of major malformations. The reported rates of major
congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background
incidence of major malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not
differ between the groups and there were no clinically significant musculoskelatal dysfunctions up to one year of
age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester
exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among
live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence
ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse
reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to
ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies, of which most
experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects
or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their
developing fetuses. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the
potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times
the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of
harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately
0.4- and 1.3-times the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal
toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed
at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing
infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking
ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing
joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment
indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric
dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to
Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to the controls, including those related to
joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract
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infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control
agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and
9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41%
(138/335) in the ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS
and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-
blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67
patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose
q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose
q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not
studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0-
93 days). This study was not designed to determine long term effects and the safety of repeated exposure to
ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the
ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients
in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and
frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten
day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without
other abnormalities eight months after treatment. However, the relationship of this event to the patient’s course of
ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age and 10%
were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of
adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for
patients greater than 65 years of age with normal renal function. However, since some older individuals experience
reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients,
and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral ciprofloxacin, 49,038
patients received courses of the drug. Most of the adverse events reported were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued
because of an adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy
durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests
abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1% of patients
treated with intravenous ciprofloxacin : nausea, diarrhea, central nervous system disturbance, local I.V. site
reactions, liver function tests abnormal eosinophilia, headache, restlessness, and rash. Many of these events were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no
treatment. Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These may appear
as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous
administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration, that occurred in
1% or less of ciprofloxacin patients are listed below:
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BODY AS A WHOLE:
abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia,
tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina pectoris,
atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression, dysphasia, phobia,
depersonalization, manic reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness,
paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal
gait, grand mal convulsion, anorexia
GASTROINTESTINAL:
ileus,
jaundice,
gastrointestinal
bleeding,
C.
difficile
associated
diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric pain,
constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence, hepatitis, painful oral
mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain, achiness, flare up of
gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal calculi, frequent
urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia, candiduria, vaginitis, breast pain.
Crystalluria, cylindruria, hematuria and albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema, respiratory
distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions, erythema multiforme/Stevens-Johnson
syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck,
conjunctivae, hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change in color
perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, chromatopsia, a
bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to
elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V. P.O. sequential) with
intravenous beta-lactam control antibiotics, the CNS adverse event profile of ciprofloxacin was comparable to that of
the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was compared to a
cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to
17 years of age (mean age of 6 + 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa
Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment
was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and
neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well
as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were
evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint
exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of
motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 %
(21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30
days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they
received I.V. or oral therapy. Ciprofloxacin-treated patients were more likely to report more than one event and on
more than one occasion compared to control patients. These events occurred in all age groups and the rates were
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consistently higher in the ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these
events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed
4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports
activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months
without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control
group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be
concluded that the ciprofloxacin group had findings comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and
somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6
weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the
comparator group. The most frequent events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared
to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated
patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse events were
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other
adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal
pain 3.3%, accidental injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in
adults during clinical trials or post-marketing experience may also occur in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide marketing
experience with quinolones, including ciprofloxacin. Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of
the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal
connection to the drug.
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Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence,
glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic necrosis, hyperesthesia, hypertonia,
hypesthesia, hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia,
monoliasis (oral, gastrointestinal, vaginal) myalgia, myasthenia, myasthenia gravis (possible exacerbation),
myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), phenytoin alteration (serum),
potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal
calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, toxic
epidermal necrolysis, triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See
PRECAUTIONS.)
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with intravenous
ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
—
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin;
Hematologic
—
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit;
Renal
—
elevations of serum creatinine, BUN, and uric acid;
Other
—
elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides.
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte count,
immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ GT), decreased
BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum potassium,
elevated serum potassium, elevated serum cholesterol. Other changes occurring rarely during administration of
ciprofloxacin were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated
sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding
diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive treatment.
Adequate hydration must be maintained. Only a small amount of ciprofloxacin (<10%) is removed from the body
after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous
doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at dosages
described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein will minimize patient
discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and nature of the
infection, the susceptibility of the causative microorganism, the integrity of the patient’s host-defense mechanisms,
and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
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Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
* used in conjunction with metronidazole. (See product labeling for prescribing information.)
† DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This indication is
based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to
predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations,
see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION. Total duration of ciprofloxacin administration
(I.V. or oral) for inhalational anthrax (post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral administration
are available. Parenteral therapy may be switched to oral CIPRO when the condition warrants, at the discretion of
the physician. (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion; however, the drug
is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These
alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended for patients with severe renal dysfunction.
The following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine
clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
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Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic insufficiency, careful
monitoring is suggested.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered orally as described in the Dosage Guidelines table. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or pyelonephritis should be
determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection
were initiated on 6 to 10 mg/kg I.V. every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12
hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 8 hours
Complicated
Urinary Tract or
Pyelonephritis
(patients from 1
to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per dose;
not to be exceeded even in
patients weighing > 51 kg)
Every 12
hours
10-21
days*
Intravenous
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)**
Oral
15 mg/kg
(maximum 500 mg per dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was
determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis
spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human
populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated
urinary tract infection and pyelonephritis. No information is available on dosing adjustments necessary for pediatric
patients with moderate to severe renal insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The intravenous dose
should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO I.V. This should be diluted
with a suitable intravenous solution to a final concentration of 1–2mg/mL. (See COMPATIBILITY AND STABILITY.)
The resulting solution should be infused over a period of 60 minutes by direct infusion or through a Y-type
intravenous infusion set which may already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily the
administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of CIPRO I.V. and
another drug is necessary each drug should be given separately in accordance with the recommended dosage and
route of administration for each drug.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in flexible containers
of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted and may be infused as
described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to concentrations of 0.5
to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is available in
200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed solution is supplied in latex-
free flexible containers as follows:
VIAL:
manufactured by Bayer Corporation and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Abbott Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Baxter Healthcare Corporation, Deerfield, IL
60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
STORAGE
Vial:
Store between 5 – 30°C (41 – 86°F).
Flexible Container:
Store between 5 – 25°C (41 – 77°F).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species
tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young
beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint.
At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin
doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon
comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by
histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with
arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from
the joint reduced the lesions but did not totally prevent them.
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Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which
predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus
monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-
times the highest recommended therapeutic dose based upon mg/m2). After 6 months of intravenous dosing at 10
mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20
mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon
mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release because they are partially
antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces
hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone and
indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in
the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving
oral and intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin pharmacokinetics have
been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in
human adults receiving 500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously
every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In a
study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3
µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute intravenous infusions of
10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally
every 12 hours achieve a mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data,
including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this
indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105)
spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin
for the anthrax strain used in this study was 0.08 µg/mL. In the animals studied, mean serum concentrations of
ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to
1.69 µg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5.
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-
exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-
treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q
4h, for the empirical therapy of febrile neutropenic patients were studied in one large pivotal multicenter,
randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological
eradication of infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of
infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to
an increased incidence of adverse events compared to controls, including events related to joints and/or
surrounding tissues.
Ciprofloxacin, administered I.V. and /or orally, was compared to a cephalosporin for treatment of complicated
urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years).
The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The
primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new
infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a
causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature
discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between
ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic
Eradication
of
the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new
infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2,
NCCLS, Wayne, PA, January, 2000. 2. National Committee for Clinical Laboratory Standards, Performance
Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-
A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and
Dermatological Drug Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD
20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in
rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6. Friedlander AM, et al. Postexposure prophylaxis against
experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of
drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a
multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339. 9. Schaefer C,
Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry
of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:
83-89.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516 USA
Rx Only
XXXXXXX 3/04
BAY q 3939
5202-4-A-U.S.-9
©2004 Bayer Pharmaceuticals Corporation
xxxxx
Printed In U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:09.504383
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19537s049,19857s031,19847se5-027,20780se5-013_cipro_lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 31}
|
11,783
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NDA 19-856/S-025
Page 3
®
SINEMET CR
(CARBIDOPA-LEVODOPA)
SUSTAINED-RELEASE TABLETS
DESCRIPTION
SINEMET* CR (Carbidopa-Levodopa) is a sustained-release combination of carbidopa and levodopa
for the treatment of Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound,
slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid
monohydrate. Its empirical formula is C10H14N2O4•H2O and its structural formula is:
CH3
CH2CCOOH • H2O
NHNH2
Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a
molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β(3,4-dihydroxybenzene)
propanoic acid. Its empirical formula is C9H11NO4 and its structural formula is: Chemical Structure
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NDA 19-856/S-025
Page 4 Chemical Structure
NH 2
*Registered trademark of MERCK & CO., INC. COPYRIGHT ©
MERCK & CO., INC., 1996 All rights reserved 1
SINEMET CR is supplied as sustained-release tablets containing either 50 mg of carbidopa and 200
mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa. Inactive ingredients: hydroxypropyl
cellulose, polyvinylacetate-crotonic acid copolymer, magnesium stearate and red ferric oxide.
SINEMET CR 50-200 also contains D&C Yellow 10.
The 50-200 tablet is supplied as an oval, scored, biconvex, compressed tablet that is peach colored.
The 25-100 tablet is supplied as an oval, biconvex, compressed tablet that is pink colored. The
SINEMET CR tablet is a polymeric-based drug delivery system that controls the release of carbidopa
and levodopa as it slowly erodes. SINEMET CR 25-100 is available to facilitate titration and as an
alternative to the half-tablet of SINEMET CR 50-200.
CLINICAL PHARMACOLOGY
Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system
affecting the mobility and control of the skeletal muscular system. Its characteristic features include
resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa
therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine
in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's
disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic
precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in
the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's
disease.
Pharmacodynamics
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues
so that only a small portion of a given dose is transported unchanged to the central nervous system. For
this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be
accompanied by nausea and other adverse reactions, some of which are attributable to dopamine
formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of
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NDA 19-856/S-025
Page 5
levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier
and does not affect the metabolism of levodopa within the central nervous system.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of
carbidopa with levodopa makes more levodopa available for transport to the brain.
Patients treated with levodopa therapy for Parkinson's disease may develop motor fluctuations
characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor
fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to
immobility. Although the causes of the motor fluctuations are not completely understood, in some
patients they may be attenuated by treatment regimens that produce steady plasma levels of levodopa.
SINEMET CR contains either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and
100 mg of levodopa in a sustained-release dosage form designed to release these ingredients over a 4-
to 6-hour period. With SINEMET CR there is less variation in plasma levodopa levels than with
SINEMET* (Carbidopa-Levodopa), the conventional formulation. However, SINEMET CR
(Carbidopa-Levodopa) Sustained-Release is less systemically bioavailable than SINEMET
(Carbidopa-Levodopa) and may require increased daily doses to achieve the same level of
symptomatic relief as provided by SINEMET (Carbidopa-Levodopa).
In clinical trials, patients with moderate to severe motor fluctuations who received SINEMET CR did
not experience quantitatively significant reductions in ‘off’ time when compared to SINEMET
(Carbidopa-Levodopa). However, global ratings of improvement as assessed by both patient and
physician were better during therapy with SINEMET CR than with SINEMET (Carbidopa-Levodopa).
In patients without motor fluctuations, SINEMET CR, under controlled conditions, provided the same
therapeutic benefit with less frequent dosing when compared to SINEMET (Carbidopa-Levodopa).
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and,
when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa,
and decreases plasma and urinary dopamine and homovanillic acid.
Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET
CR, the apparent half-life of levodopa may be prolonged because of continuous absorption.
In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a
single dose of SINEMET CR 50-200 was about 2 hours as compared to
0.5 hours after standard SINEMET (Carbidopa-Levodopa). The maximum concentration of levodopa
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NDA 19-856/S-025
Page 6
after a single dose of SINEMET CR was about 35% of the standard SINEMET (Carbidopa-Levodopa)
(1151 vs. 3256 ng/mL). The extent of availability of levodopa from SINEMET CR was about 70-75%
relative to intravenous levodopa or standard SINEMET (Carbidopa-Levodopa) in the elderly. The
absolute bioavailability of levodopa from SINEMET CR (relative to I.V.) in young subjects was shown
to be only about 44%. The extent of availability and the peak concentrations of levodopa were
comparable in the elderly after a single dose and at steady state after t.i.d. administration of SINEMET
CR 50-200. In elderly subjects, the average trough levels of levodopa at steady state after the CR tablet
were about 2 fold higher than after the standard SINEMET (Carbidopa-Levodopa) (163 vs. 74 ng/mL).
In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with
SINEMET CR fluctuated in a narrower range than with SINEMET (Carbidopa-Levodopa). Because
the bioavailability of levodopa from SINEMET CR relative to SINEMET (Carbidopa-Levodopa) is
approximately 70-75%, the daily dosage of levodopa necessary to produce a given clinical response
with the sustained-release formulation will usually be higher.
The extent of availability and peak concentrations of levodopa after a single dose of SINEMET CR 50
200 increased by about 50% and 25%, respectively, when administered with food.
At steady state, the bioavailability of carbidopa from SINEMET Tablets is approximately 99% relative
to the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability
from SINEMET CR 50-200 is approximately 58% relative to that from SINEMET.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of
levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action
of pyridoxine.
INDICATIONS AND USAGE
SINEMET CR is indicated in the treatment of the symptoms of idiopathic Parkinson's disease
(paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow
injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.
CONTRAINDICATIONS
Nonselective MAO inhibitors are contraindicated for use with SINEMET CR. These inhibitors must be
discontinued at least two weeks prior to initiating therapy with SINEMET CR. SINEMET CR may be
administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with
selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS: Drug Interactions).
SINEMET CR is contraindicated in patients with known hypersensitivity to any component of this
drug and in patients with narrow-angle glaucoma.
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NDA 19-856/S-025
Page 7
Because levodopa may activate a malignant melanoma, SINEMET CR should not be used in patients
with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS
When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be
discontinued at least twelve hours before SINEMET CR is started. In order to reduce adverse
reactions, it is necessary to individualize therapy. SINEMET CR should be substituted at a dosage that
will provide approximately 25% of the previous levodopa dosage (see DOSAGE AND
ADMINISTRATION).
Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more
levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor,
certain adverse CNS effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy
with SINEMET CR (Carbidopa-Levodopa) Sustained-Release than with levodopa alone.
Patients receiving SINEMET CR may develop increased dyskinesias compared to SINEMET
(Carbidopa-Levodopa). Dyskinesias are a common side effect of carbidopalevodopa treatment. The
occurrence of dyskinesias may require dosage reduction.
As with levodopa, SINEMET CR may cause mental disturbances. These reactions are thought to be
due to increased brain dopamine following administration of levodopa. All patients should be observed
carefully for the development of depression with concomitant suicidal tendencies. Patients with past or
current psychoses should be treated with caution.
SINEMET CR should be administered cautiously to patients with severe cardiovascular or pulmonary
disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering SINEMET CR to patients with a history
of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients,
cardiac function should be monitored with particular care during the period of initial dosage
adjustment, in a facility with provisions for intensive cardiac care.
As with levodopa, treatment with SINEMET CR may increase the possibility of upper gastrointestinal
hemorrhage in patients with a history of peptic ulcer.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of a symptom complex resembling NMS have been reported in association with dose
reductions or withdrawal of SINEMET and SINEMET CR.
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NDA 19-856/S-025
Page 8
Therefore, patients should be observed carefully when the dosage of SINEMET CR is reduced
abruptly or discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered consciousness,
mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea,
sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation,
leukocytosis, myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia,
systemic infection, etc.) is essential. This may be especially complex if the clinical presentation
includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis include central
anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring
and 2) treatment of any concomitant serious medical problems for which specific treatments are
available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are
often used in the treatment of NMS; however, their effectiveness has not been demonstrated in
controlled studies.
PRECAUTIONS
General
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function
are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET CR provided the
intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular
pressure during therapy.
Dopaminergic agents, including levodopa, may be associated with somnolence and very rarely
episodes of sudden onset of sleep. In some cases, these episodes may occur without awareness or
warning during daily activities. Patients must be informed of this and advised to exercise caution while
driving or operating machines while being treated with dopaminergic agents, including levodopa.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines (see Information for Patients).
Melanoma
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NDA 19-856/S-025
Page 9
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to
approximately 6-fold higher) of developing melanoma than the general population. Whether the
increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat
Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently
and on a regular basis when using SINEMET CR for any indication. Ideally, periodic skin
examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET CR is a sustained-release formulation of carbidopa
levodopa which releases these ingredients over a 4- to 6-hour period. It is important that SINEMET
CR be taken at regular intervals according to the schedule outlined by the physician. The patient
should be cautioned not to change the prescribed dosage regimen and not to add any additional
antiparkinson medications, including other carbidopa-levodopa preparations, without first consulting
the physician.
If abnormal involuntary movements appear or get worse during treatment with SINEMET CR, the
physician should be notified, as dosage adjustment may be necessary.
Patients should be advised that sometimes the onset of effect of the first morning dose of SINEMET
CR may be delayed for up to 1 hour compared with the response usually obtained from the first
morning dose of SINEMET (Carbidopa-Levodopa). The physician should be notified if such delayed
responses pose a problem in treatment.
Patients should be advised that, occasionally, dark color (red, brown, or black) may appear in saliva,
urine, or sweat after ingestion of SINEMET CR. Although the color appears to be clinically
insignificant, garments may become discolored.
The patient should be informed that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also
delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin
tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce
the clinical effectiveness of the levodopa or carbidopa-levodopa therapy.
Patients must be advised that the whole or half tablet should be swallowed without chewing or
crushing.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some
cases without awareness or warning signs, when they are taking dopaminergic agents, including
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NDA 19-856/S-025
Page 10
levodopa. Patients should be advised to exercise caution while driving or operating machinery and that
if they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities.
(See PRECAUTIONS: General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and
other intense urges and the inability to control these urges while taking one or more of the medications
that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s
disease, including SINEMET CR. Although it is not proven that the medications caused these events,
these urges were reported to have stopped in some cases when the dose was reduced or the medication
was stopped. Prescribers should ask patients about the development of new or increased gambling
urges, sexual urges or other urges while being treated with SINEMET CR. Patients should inform their
physician if they experience new or increased gambling urges, increased sexual urges or other intense
urges while taking SINEMET CR. Physicians should consider dose reduction or stopping the
medication if a patient develops such urges while taking SINEMET CR.
NOTE: The suggested advice to patients being treated with SINEMET CR is intended to aid in the safe
and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood
urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea
nitrogen, creatinine, and uric acid are lower during administration of carbidopa-levodopa preparations
than with levodopa.
Carbidopa-levodopa preparations, such as SINEMET (Carbidopa-Levodopa) and SINEMET CR, may
cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of
ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may
result with the use of glucose-oxidase methods of testing for glucosuria.
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa-levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of
catecholamines and their metabolites in patients on levodopa or carbidopa-levodopa therapy.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with SINEMET
CR (Carbidopa-Levodopa) Sustained-Release.
Symptomatic postural hypotension has occurred when carbidopa-levodopa preparations were added to
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-856/S-025
Page 11
the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with
SINEMET CR is started, dosage adjustment of the antihypertensive drug may be required.
For
patients
receiving
monoamine
oxidase
(MAO)
inhibitors
(Type
A
or
B),
see
CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be
associated with severe orthostatic hypotension not attributable to carbidopalevodopa alone (see
CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting
from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid
may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in
Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking
these drugs with SINEMET CR should be carefully observed for loss of therapeutic response.
Iron salts may reduce the bioavailability of levodopa and carbidopa. The clinical relevance is unclear.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying,
metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic
properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year bioassay of SINEMET (Carbidopa-Levodopa), no evidence of carcinogenicity was found
in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and
four times the maximum daily human dose of levodopa (equivalent to 8 SINEMET CR tablets).
In reproduction studies with SINEMET (Carbidopa-Levodopa), no effects on fertility were found in
rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four
times the maximum daily human dose of levodopa (equivalent to 8 SINEMET CR tablets).
Pregnancy
Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20
times the maximum recommended human dose of SINEMET (Carbidopa-Levodopa). There was a
decrease in the number of live pups delivered by rats receiving approximately two times the maximum
recommended human dose of carbidopa and approximately five times the maximum recommended
human dose of levodopa during organogenesis. SINEMET (Carbidopa-Levodopa) caused both visceral
and skeletal malformations in rabbits at all doses and ratios of carbidopa/levodopa tested, which
ranged from 10 times/5 times the maximum recommended human dose of carbidopa/levodopa to 20
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NDA 19-856/S-025
Page 12
times/10 times the maximum recommended human dose of carbidopa/levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from
individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.
Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET CR in women of
childbearing potential requires that the anticipated benefits of the drug be weighed against possible
hazards to mother and child.
Nursing Mothers
In a study of one nursing mother with Parkinson’s disease, excretion of levodopa in human breast milk
was reported. Therefore, caution should be exercised when SINEMET CR is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients
below the age of 18 is not recommended.
ADVERSE REACTIONS
In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while
on SINEMET (Carbidopa-Levodopa) were randomized to therapy with either SINEMET (Carbidopa-
Levodopa) or SINEMET CR. The adverse experience frequency profile of SINEMET CR did not
differ substantially from that of SINEMET (Carbidopa-Levodopa), as shown in Table I.
Table I:
Clinical Adverse Experiences Occurring in 1% or Greater of Patients
SINEMET CR SINEMET (Carbidopa-Levodopa) n = 491 n = 524 Adverse Experience % %
Dyskinesia 16.5 12.2 Nausea 5.5 5.7 Hallucinations 3.9 3.2 Confusion 3.7 2.3 Dizziness 2.9 2.3 Depression 2.2 1.3
Urinary tract infection 2.2 2.3 Headache 2.0 1.9 Dream abnormalities 1.8 0.8 Dystonia 1.8 0.8 Vomiting 1.8 1.9 Upper
respiratory infection 1.8 1.0 Dyspnea 1.6 0.4 ‘On-Off’ phenomena 1.6 1.1 Back pain 1.6 0.6 Dry mouth 1.4 1.1
Anorexia 1.2 1.1 Diarrhea 1.2 0.6 Insomnia 1.2 1.0 Orthostatic hypotension 1.0 1.1 Shoulder pain 1.0 0.6 Chest pain
1.0 0.8 Muscle cramps 0.8 1.0 Paresthesia 0.8 1.1 Urinary frequency 0.8 1.1 Dyspepsia 0.6 1.1 Constipation 0.2 1.5
Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients
who received SINEMET CR and 475 who received SINEMET (Carbidopa-Levodopa) during
controlled clinical trials included: decreased hemoglobin and hematocrit; elevated serum glucose;
white blood cells, bacteria and blood in the urine.
The adverse experiences observed in patients in uncontrolled studies were similar to those
seen in controlled clinical studies.
Other adverse experiences reported overall in clinical trials in 748 patients treated with
SINEMET CR, listed by body system in order of decreasing frequency, include:
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NDA 19-856/S-025
Page 13
Body as a Whole: Asthenia, fatigue, abdominal pain, orthostatic effects.
Cardiovascular: Palpitation, hypertension, hypotension, myocardial infarction.
Gastrointestinal: Gastrointestinal pain, dysphagia, heartburn.
Metabolic: Weight loss.
Musculoskeletal: Leg pain.
Nervous System/Psychiatric: Chorea, somnolence, falling, anxiety, disorientation,
decreased mental acuity, gait abnormalities, extrapyramidal disorder, agitation,
nervousness, sleep disorders, memory impairment.
Respiratory: Cough, pharyngeal pain, common cold.
Skin: Rash.
Special Senses: Blurred vision.
Urogenital: Urinary incontinence.
Laboratory Tests: Decreased white blood cell count and serum potassium; increased
BUN, serum creatinine and serum LDH; protein and glucose in the urine.
The following adverse experiences have been reported in post-marketing experience with
SINEMET CR:
Cardiovascular: Cardiac irregularities, syncope.
Gastrointestinal: Taste alterations, dark saliva.
Hypersensitivity: Angioedema, urticaria, pruritus, bullous lesions (including pemphigus-like reactions).
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Page 14
Nervous System/Psychiatric: Neuroleptic malignant syndrome (see WARNINGS), increased tremor,
peripheral neuropathy, psychotic episodes including delusions and paranoid ideation, increased libido.
Skin: Alopecia, flushing, dark sweat.
Urogenital: Dark urine.
Other adverse reactions that have been reported with levodopa alone and with various carbidopa
levodopa formulations and may occur with SINEMET CR are:
Cardiovascular: Phlebitis.
Gastrointestinal: Gastrointestinal bleeding, development of duodenal ulcer, sialorrhea, bruxism,
hiccups, flatulence, burning sensation of tongue.
Hematologic: Hemolytic and nonhemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.
Hypersensitivity: Henoch-Schonlein purpura.
Metabolic: Weight gain, edema.
Nervous System/Psychiatric: Ataxia, depression with suicidal tendencies, dementia, euphoria,
convulsions (however, a causal relationship has not been established); bradykinetic episodes,
numbness, muscle twitching, blepharospasm (which may be taken as an early sign of excess dosage;
consideration of dosage reduction may be made at this time), trismus, activation of latent Horner's
syndrome, nightmares.
Skin: Malignant melanoma (see also CONTRAINDICATIONS), increased sweating. Special
Senses: Oculogyric crises, mydriasis, diplopia. Urogenital: Urinary retention, priapism.
Miscellaneous: Faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing
patterns.
Laboratory Tests: Abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), bilirubin,
Coombs test, uric acid.
OVERDOSAGE
Management of acute overdosage with SINEMET CR is the same as with levodopa. Pyridoxine is not
effective in reversing the actions of SINEMET CR.
General supportive measures should be employed, along with immediate gastric lavage. Intravenous
fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic
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NDA 19-856/S-025
Page 15
monitoring should be instituted and the patient carefully observed for the development of arrhythmias;
if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may
have taken other drugs as well as SINEMET CR should be taken into consideration. To date, no
experience has been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant
proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are
expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of
800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of
carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a
significant proportion of mice are expected to die to 3360 mg/kg.
DOSAGE AND ADMINISTRATION
SINEMET CR contains carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100
tablet. The daily dosage of SINEMET CR must be determined by careful titration. Patients should be
monitored closely during the dose adjustment period, particularly with regard to appearance or
worsening of involuntary movements, dyskinesias or nausea. SINEMET CR 50-200 may be
administered as whole or as half-tablets which should not be chewed or crushed. SINEMET CR 25
100 may be used in combination with SINEMET CR 50-200 to titrate to the optimum dosage, or as an
alternative to the 50-200 half-tablet.
Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be
used concomitantly while SINEMET CR is being administered, although their dosage may have to be
adjusted.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, SINEMET CR can be
given to patients receiving supplemental pyridoxine (vitamin B6).
Initial Dosage
Patients currently treated with conventional carbidopa-levodopa preparations: Studies show that
peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and
greater. Because the bioavailabilities of carbidopa and levodopa in SINEMET and SINEMET CR are
different, appropriate adjustments should be made, as shown in Table II.
Table II: Approximate Bioavailabilities at Steady State
†
Amount of
Approximate
Approximate Amount
Levodopa (mg)
Bioavailability
of Bioavailable
Tablet
in Each Tablet
Levodopa (mg) in
Each Tablet
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NDA 19-856/S-025
Page 16
SINEMET CR
50-200
200
0.70-0.75††
140-150
SINEMET
25-100
100
0.99†††
99
†
This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient
variabilities may affect the bioavailability of carbidopa and levodopa.
†† The extent of availability of levodopa from SINEMET CR was about 70-75% relative to intravenous levodopa or
standard SINEMET (Carbidopa-Levodopa) in the elderly.
†††The extent of availability of levodopa from SINEMET was 99% relative to intravenous levodopa in the healthy elderly.
Dosage with SINEMET CR should be substituted at an amount that provides approximately 10% more
levodopa per day, although this may need to be increased to a dosage that provides up to 30% more
levodopa per day depending on clinical response (see DOSAGE AND ADMINISTRATION:
Titration with SINEMET CR). The interval between doses of SINEMET CR should be 4-8 hours
during the waking day. (See CLINICAL PHARMACOLOGY: Pharmacodynamics.)
A guideline for initiation of SINEMET CR is shown in Table III.
Table III: Guidelines for Initial Conversion from SINEMET (Carbidopa-Levodopa) to
SINEMET CR
SINEMET (Carbidopa-SINEMET CR Levodopa) *
Total Daily Dose Suggested
Levodopa (mg) Dosage Regimen
300-400
200 mg b.i.d.
500-600
300 mg b.i.d. or 200 mg t.i.d.
700-800
A total of 800 mg in 3 or more divided doses (e.g., 300 mg a.m., 300 mg
early p.m., and 200 mg later p.m.)
900-1000
A total of 1000 mg in 3 or more divided doses (e.g., 400 mg a.m., 400 mg
early p.m., and 200 mg later p.m.)
*For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION: Initial Dosage — Patients currently
treated with conventional carbidopa-levodopa preparations.
Patients currently treated with levodopa without a decarboxylase inhibitor: Levodopa must be
discontinued at least twelve hours before therapy with SINEMET CR is started. SINEMET CR should
be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In
patients with mild to moderate disease, the initial dose is usually 1 tablet of SINEMET CR 50-200
b.i.d.
Patients not receiving levodopa: In patients with mild to moderate disease, the initial recommended
dose is 1 tablet of SINEMET CR 50-200 b.i.d. Initial dosage should not be given at intervals of less
than 6 hours.
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NDA 19-856/S-025
Page 17
Titration with SINEMET CR
Following initiation of therapy, doses and dosing intervals may be increased or decreased depending
upon therapeutic response. Most patients have been adequately treated with doses of SINEMET CR
that provide 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging
from 4 to 8 hours during the waking day. Higher doses of SINEMET CR (2400 mg or more of
levodopa per day) and shorter intervals (less than 4 hours) have been used, but are not usually
recommended.
When doses of SINEMET CR are given at intervals of less than 4 hours, and/or if the divided doses are
not equal, it is recommended that the smaller doses be given at the end of the day.
An interval of at least 3 days between dosage adjustments is recommended.
Maintenance
Because Parkinson's disease is progressive, periodic clinical evaluations are recommended; adjustment
of the dosage regimen of SINEMET CR may be required.
Addition of Other Antiparkinson Medications
Anticholinergic agents, dopamine agonists, and amantadine can be given with SINEMET CR. Dosage
adjustment of SINEMET CR may be necessary when these agents are added.
A dose of SINEMET (Carbidopa-Levodopa) 25-100 or 10-100 (one half or a whole tablet) can be
added to the dosage regimen of SINEMET CR in selected patients with advanced disease who need
additional immediate-release levodopa for a brief time during daytime hours.
Interruption of Therapy
Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been
associated with dose reductions and withdrawal of SINEMET (Carbidopa-Levodopa) or SINEMET
CR.
Patients should be observed carefully if abrupt reduction or discontinuation of SINEMET CR is
required, especially if the patient is receiving neuroleptics. (See WARNINGS.)
If general anesthesia is required, SINEMET CR may be continued as long as the patient is permitted to
take oral medication. If therapy is interrupted temporarily, the patient should be observed for
symptoms resembling NMS, and the usual dosage should be administered as soon as the patient is able
to take oral medication.
HOW SUPPLIED
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NDA 19-856/S-025
Page 18
SINEMET CR 50-200 (Carbidopa-Levodopa) Sustained-Release Tablets containing 50 mg of
carbidopa and 200 mg of levodopa, are peach colored, oval, biconvex, compressed tablets, that are
scored and coded “521” on one side and SINEMET CR on the other side. They are supplied as
follows:
NDC
0056-0521-68
bottles
of
100
NDC
0056-0521-85
bottles
of
500.
SINEMET CR 25-100 (Carbidopa-Levodopa) Sustained-Release Tablets containing 25 mg of
carbidopa and 100 mg of levodopa, are pink colored, oval, biconvex, compressed tablets, that are
coded “601” (with bar) on one side and SINEMET CR on the other side. They are supplied as follows:
NDC 0056-0601-68 bottles of 100.
Storage
Store below 30°C (86°F). Store in a tightly closed container.
Manufactured by:
MERCK & CO., INC.
Whitehouse Station, NJ 08889, USA logo
Princeton, NJ 08543 USA
Co. Print Code Co. Print Code Printed in USA Rev TBD
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:09.587881
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019856s025lbl.pdf', 'application_number': 19856, 'submission_type': 'SUPPL ', 'submission_number': 25}
|
11,784
|
SINEMET
® CR
(carbidopa levodopa)
Sustained-Release Tablets
DESCRIPTION
SINEMET® CR (carbidopa levodopa) is a sustained-release combination of carbidopa and levodopa for
the treatment of Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound,
slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is
C10H14N2O4•H2O, and its structural formula is:
Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a
molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene)
propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is:
SINEMET CR is supplied as sustained-release tablets containing either 50 mg of carbidopa and
200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa. Inactive ingredients are
hydroxypropyl cellulose, magnesium stearate, and hypromellose. SINEMET CR 25-100 and SINEMET CR
50-200 also contain FD&C Blue #2/Indigo Carmine AL and FD&C Red #40/Allura Red AC AL.
The 50-200 tablet is supplied as an oval, compressed tablet that is dappled-purple in color and is
coded "521" on one side and plain on the other. The 25-100 tablet is supplied as an oval, compressed
tablet that is dappled-purple in color and is coded "601" on one side and plain on the other. The SINEMET
CR tablet is a polymeric-based drug delivery system that controls the release of carbidopa and levodopa
as it slowly erodes. SINEMET CR 25-100 is available to facilitate titration when 100 mg steps are required.
CLINICAL PHARMACOLOGY
Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous
system affecting the mobility and control of the skeletal muscular system. Its characteristic features
include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa
therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine
in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease
1
Reference ID: 3594908
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apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor
of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
Pharmacodynamics
W hen levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues
so that only a small portion of a given dose is transported unchanged to the central nervous system. For
this reason, large doses of levodopa are required for adequate therapeutic effect, and these may often be
accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed
in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of
levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and
does not affect the metabolism of levodopa within the central nervous system.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa
with levodopa makes more levodopa available for transport to the brain.
Patients treated with levodopa therapy for Parkinson's disease may develop motor fluctuations
characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor
fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility.
Although the causes of the motor fluctuations are not completely understood, in some patients they may
be attenuated by treatment regimens that produce steady plasma levels of levodopa.
SINEMET CR contains either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and
100 mg of levodopa in a sustained-release dosage form designed to release these ingredients over a 4- to
6-hour period. W ith SINEMET CR there is less variation in plasma levodopa levels than with SINEMET
(carbidopa levodopa) immediate release tablets, the conventional formulation. However, SINEMET CR is
less systemically bioavailable than SINEMET and may require increased daily doses to achieve the same
level of symptomatic relief as provided by SINEMET.
In clinical trials, patients with moderate to severe motor fluctuations who received SINEMET CR did not
experience quantitatively significant reductions in ‘off’ time when compared to SINEMET. However, global
ratings of improvement as assessed by both patient and physician were better during therapy with
SINEMET CR than with SINEMET. In patients without motor fluctuations, SINEMET CR, under controlled
conditions, provided the same therapeutic benefit with less frequent dosing when compared to SINEMET.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and,
when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and
decreases plasma and urinary dopamine and homovanillic acid.
Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET
CR, the apparent half-life of levodopa may be prolonged because of continuous absorption.
In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a
single dose of SINEMET CR 50-200 was about 2 hours as compared to 0.5 hours after standard
SINEMET. The maximum concentration of levodopa after a single dose of SINEMET CR was about 35%
of the standard SINEMET (1151 vs. 3256 ng/mL). The extent of availability of levodopa from SINEMET
CR was about 70-75% relative to intravenous levodopa or standard SINEMET in the elderly. The absolute
bioavailability of levodopa from SINEMET CR (relative to I.V.) in young subjects was shown to be only
about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the
elderly after a single dose and at steady state after t.i.d. administration of SINEMET CR 50-200. In elderly
subjects, the average trough levels of levodopa at steady state after the CR tablet were about 2 fold higher
than after the standard SINEMET (163 vs. 74 ng/mL).
In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with
SINEMET CR fluctuated in a narrower range than with SINEMET. Because the bioavailability of levodopa
from SINEMET CR relative to SINEMET is approximately 70-75%, the daily dosage of levodopa
necessary to produce a given clinical response with the sustained-release formulation will usually be
higher.
The extent of availability and peak concentrations of levodopa after a single dose of SINEMET CR 50
200 increased by about 50% and 25%, respectively, when administered with food.
2
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
At steady state, the bioavailability of carbidopa from SINEMET Tablets is approximately 99% relative to
the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability from
SINEMET CR 50-200 is approximately 58% relative to that from SINEMET.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of
levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of
pyridoxine.
Special Populations
Geriatric: A study in eight young healthy subjects (21-22 yr) and eight elderly healthy subjects (69-76
yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects
following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of
levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study
in forty patients with Parkinson’s disease, there was a correlation between age of patients and the
increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa
decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 yr) compared to young
patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients
(≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS, Geriatric Use).
The AUC of carbidopa was increased in elderly subjects (n=10, 65-76 yr) by 29% compared to young
subjects (n=24, 23-64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This
increase is not considered a clinically significant impact.
INDICATIONS AND USAGE
SINEMET CR is indicated in the treatment of Parkinson's disease, post-encephalitic parkinsonism, and
symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.
CONTRAINDICATIONS
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with SINEMET CR.
These inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET CR.
SINEMET CR may be administered concomitantly with the manufacturer's recommended dose of an MAO
inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS, Drug Interactions).
SINEMET CR is contraindicated in patients with known hypersensitivity to any component of this drug,
and in patients with narrow-angle glaucoma.
WARNINGS
When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be
discontinued at least twelve hours before SINEMET CR is started. In order to reduce adverse
reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION section
before initiating therapy.
SINEMET CR should be substituted at a dosage that will provide approximately 25% of the previous
levodopa dosage (see DOSAGE AND ADMINISTRATION).
Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more
levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain
adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner
during therapy with SINEMET CR than with levodopa alone.
Patients receiving SINEMET CR may develop increased dyskinesias compared to SINEMET.
Dyskinesias are a common side effect of carbidopa levodopa treatment. The occurrence of dyskinesias
may require dosage reduction.
All patients should be observed carefully for the development of depression with concomitant suicidal
tendencies.
3
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET CR should be administered cautiously to patients with severe cardiovascular or pulmonary
disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering SINEMET CR to patients with a history of
myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac
function should be monitored with particular care during the period of initial dosage adjustment, in a facility
with provisions for intensive cardiac care.
As with levodopa, treatment with SINEMET CR may increase the possibility of upper gastrointestinal
hemorrhage in patients with a history of peptic ulcer.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking SINEMET CR alone or with other dopaminergic drugs have reported suddenly falling
asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of
motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although
many patients reported somnolence while on dopaminergic medications, there have been reports of road
traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning
signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre
existing somnolence, although some patients may not give such a history. For this reason, prescribers
should reassess patients for drowsiness or sleepiness especially since some of the events occur well after
the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or
sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients
should be advised to exercise caution while driving or operating machines during treatment with SINEMET
CR. Patients who have already experienced somnolence or an episode of sudden sleep onset should not
participate in these activities during treatment with SINEMET CR.
Before initiating treatment with SINEMET CR, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with SINEMET
CR such as the use of concomitant sedating medications and the presence of sleep disorders. Consider
discontinuing SINEMET CR in patients who report significant daytime sleepiness or episodes of falling
asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with
SINEMET CR continues, patients should be advised not to drive and to avoid other potentially dangerous
activities that might result in harm if the patients become somnolent. There is insufficient information to
establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily
living.
Hyperpyrexia and Confusion
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been
reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as
levodopa, carbidopa levodopa and carbidopa levodopa extended release. Therefore, patients should be
observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the
patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental
status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating,
hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis,
myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic
infection, etc.) is essential. This may be especially complex if the clinical presentation includes both
serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system (CNS) pathology.
4
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring
and 2) treatment of any concomitant serious medical problems for which specific treatments are available.
Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in
the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are
recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET CR provided the
intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular
pressure during therapy.
Dyskinesia
Levodopa alone, as well as SINEMET CR, is associated with dyskinesias. The occurrence of
dyskinesias may require dosage reduction.
Hallucinations / Psychotic-Like Behavior
Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In
general, hallucinations present shortly after the initiation of therapy and may be responsive to dose
reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep
disorder (insomnia) and excessive dreaming.
SINEMET CR may have similar effects on thinking and behavior. This abnormal thinking and behavior
may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion,
psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with SINEMET CR, because
of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may
exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of SINEMET CR.
Impulse Control / Compulsive Behaviors
Reports of patients taking dopaminergic medications (medications that increase central dopaminergic
tone), suggest that patients may experience an intense urge to gamble, increased sexual urges, intense
urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. In
some cases, although not all, these urges were reported to have stopped when the dose was reduced or
the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is
important for prescribers to specifically ask patients or the caregivers about the development of new or
increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with
SINEMET CR. Physicians should consider dose reduction or stopping the medication if a patient develops
such urges while taking SINEMET CR [see Information for Patients].
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to
approximately 6-fold higher) of developing melanoma than the general population. W hether the increased
risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s
disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently
and on a regular basis when using SINEMET CR for any indication. Ideally, periodic skin examinations
should be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET CR is a sustained-release formulation of carbidopa
levodopa which releases these ingredients over a 4- to 6-hour period. It is important that SINEMET CR be
taken at regular intervals according to the schedule outlined by the physician. The patient should be
cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson
medications, including other carbidopa levodopa preparations, without first consulting the physician.
5
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If abnormal involuntary movements appear or get worse during treatment with SINEMET CR, the
physician should be notified, as dosage adjustment may be necessary.
Patients should be advised that sometimes the onset of effect of the first morning dose of SINEMET
CR may be delayed for up to 1 hour compared with the response usually obtained from the first morning
dose of SINEMET. The physician should be notified if such delayed responses pose a problem in
treatment.
Patients should be advised that, occasionally, dark color (red, brown, or black) may appear in saliva,
urine, or sweat after ingestion of SINEMET CR. Although the color appears to be clinically insignificant,
garments may become discolored.
The patient should be informed that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also
delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin
tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the
clinical effectiveness of the levodopa or carbidopa levodopa therapy.
Patients must be advised that the whole or half tablet should be swallowed without chewing or
crushing.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some
cases without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if
they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities.
(See W ARNINGS, Falling Asleep During Activities of Daily Living and Somnolence.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment of
Parkinson’s disease, including SINEMET CR. Although it is not proven that the medications caused these
events, these urges were reported to have stopped in some cases when the dose was reduced or the
medication was stopped. Prescribers should ask patients about the development of new or increased
gambling urges, sexual urges or other urges while being treated with SINEMET CR. Patients should
inform their physician if they experience new or increased gambling urges, increased sexual urges, or
other intense urges while taking SINEMET CR. Physicians should consider dose reduction or stopping the
medication if a patient develops such urges while taking SINEMET CR. (See PRECAUTIONS, Impulse
Control / Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in
blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of blood
urea nitrogen, creatinine, and uric acid are lower during administration of carbidopa levodopa preparations
than with levodopa.
Carbidopa levodopa preparations, such as SINEMET and SINEMET CR, may cause a false-positive
reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction
will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose
oxidase methods of testing for glucosuria.
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of
catecholamines and their metabolites in patients on levodopa or carbidopa levodopa therapy.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with
SINEMET CR.
Symptomatic postural hypotension has occurred when carbidopa levodopa preparations were added to
the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with
SINEMET CR is started, dosage adjustment of the antihypertensive drug may be required.
For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS. Concomitant therapy
with selegiline and carbidopa levodopa may be associated with severe orthostatic hypotension not
attributable to carbidopa levodopa alone (see CONTRAINDICATIONS).
6
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting
from the concomitant use of tricyclic antidepressants and carbidopa levodopa preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid
may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in
Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking
these drugs with SINEMET CR should be carefully observed for loss of therapeutic response.
Use of SINEMET CR with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other
drugs known to deplete monoamine stores is not recommended.
SINEMET CR and iron salts or multivitamins containing iron salts should be coadministered with
caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the
bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying,
metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic
properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses
of approximately two times the maximum daily human dose of carbidopa and four times the maximum
daily human dose of levodopa (equivalent to 8 SINEMET CR tablets).
In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of
approximately two times the maximum daily human dose of carbidopa and four times the maximum daily
human dose of levodopa (equivalent to 8 SINEMET CR tablets).
Pregnancy
Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20 times
the maximum recommended human dose of SINEMET. There was a decrease in the number of live pups
delivered by rats receiving approximately two times the maximum recommended human dose of
carbidopa and approximately five times the maximum recommended human dose of levodopa during
organogenesis. SINEMET caused both visceral and skeletal malformations in rabbits at all doses and
ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended
human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of
carbidopa/levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from
individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.
Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET CR in women of
childbearing potential requires that the anticipated benefits of the drug be weighed against possible
hazards to mother and child.
Nursing Mothers
Levodopa has been detected in human milk. Caution should be exercised when SINEMET CR is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients
below the age of 18 is not recommended.
Geriatric Use
In the clinical efficacy trials for SINEMET, almost half of the patients were older than 65, but few were
older than 75. No overall meaningful differences in safety or effectiveness were observed between these
subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions
such as hallucinations cannot be ruled out. There is no specific dosing recommendation based upon
clinical pharmacology data as SINEMET and SINEMET CR are titrated as tolerated for clinical effect.
7
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on
SINEMET were randomized to therapy with either SINEMET or SINEMET CR. The adverse experience
frequency profile of SINEMET CR did not differ substantially from that of SINEMET, as shown in Table 1.
Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients
SINEMET CR
SINEMET
n=491
n=524
Adverse Experience
%
%
Dyskinesia
16.5
12.2
Nausea
5.5
5.7
Hallucinations
3.9
3.2
Confusion
3.7
2.3
Dizziness
2.9
2.3
Depression
2.2
1.3
Urinary tract infection
2.2
2.3
Headache
2.0
1.9
Dream abnormalities
1.8
0.8
Dystonia
1.8
0.8
Vomiting
1.8
1.9
Upper respiratory infection
1.8
1.0
Dyspnea
1.6
0.4
‘On-Off’ phenomena
1.6
1.1
Back pain
1.6
0.6
Dry mouth
1.4
1.1
Anorexia
1.2
1.1
Diarrhea
1.2
0.6
Insomnia
1.2
1.0
Orthostatic hypotension
1.0
1.1
Shoulder pain
1.0
0.6
Chest pain
1.0
0.8
Muscle cramps
0.8
1.0
Paresthesia
0.8
1.1
Urinary frequency
0.8
1.1
Dyspepsia
0.6
1.1
Constipation
0.2
1.5
Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients
who received SINEMET CR and 475 who received SINEMET during controlled clinical trials included:
decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood in
the urine.
The adverse experiences observed in patients in uncontrolled studies were similar to those seen in
controlled clinical studies.
Other adverse experiences reported overall in clinical trials in 748 patients treated with SINEMET CR,
listed by body system in order of decreasing frequency, include:
Body as a Whole
Asthenia, fatigue, abdominal pain, orthostatic effects.
Cardiovascular
Palpitation, hypertension, hypotension, myocardial infarction.
Gastrointestinal
Gastrointestinal pain, dysphagia, heartburn.
Metabolic
W eight loss.
Musculoskeletal
Leg pain.
8
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nervous System/Psychiatric
Chorea, somnolence, falling, anxiety, disorientation, decreased mental acuity, gait abnormalities,
extrapyramidal disorder, agitation, nervousness, sleep disorders, memory impairment.
Respiratory
Cough, pharyngeal pain, common cold.
Skin
Rash.
Special Senses
Blurred vision.
Urogenital
Urinary incontinence.
Laboratory Tests
Decreased white blood cell count and serum potassium; increased BUN, serum creatinine and serum
LDH; protein and glucose in the urine.
The following adverse experiences have been reported in postmarketing experience with SINEMET
CR:
Cardiovascular
Cardiac irregularities, syncope.
Gastrointestinal
Taste alterations, dark saliva.
Hypersensitivity
Angioedema, urticaria, pruritus, bullous lesions (including pemphigus-like reactions).
Nervous System/Psychiatric
Increased tremor, peripheral neuropathy, psychotic episodes including delusions and paranoid
ideation, pathological gambling, increased libido including hypersexuality, impulse control symptoms.
Skin
Alopecia, flushing, dark sweat.
Urogenital
Dark urine.
Other adverse reactions that have been reported with levodopa alone and with various carbidopa
levodopa formulations and may occur with SINEMET CR are:
Cardiovascular
Phlebitis.
Gastrointestinal
Gastrointestinal bleeding, development of duodenal ulcer, sialorrhea, bruxism, hiccups, flatulence,
burning sensation of tongue.
Hematologic
Hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.
Hypersensitivity
Henoch-Schönlein purpura.
Metabolic
Weight gain, edema.
Nervous System/Psychiatric
Ataxia, depression with suicidal tendencies, dementia, euphoria, convulsions (however, a causal
relationship has not been established); bradykinetic episodes, numbness, muscle twitching,
blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage
reduction may be made at this time), trismus, activation of latent Horner's syndrome, nightmares.
Skin
Malignant melanoma (see also CONTRAINDICATIONS), increased sweating.
Special Senses
Oculogyric crises, mydriasis, diplopia.
Urogenital
Urinary retention, priapism.
9
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Miscellaneous
Faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing patterns.
Laboratory Tests
Abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), bilirubin, Coombs test, uric acid.
OVERDOSAGE
Management of acute overdosage with SINEMET CR is the same as with levodopa. Pyridoxine is not
effective in reversing the actions of SINEMET CR.
General supportive measures should be employed, along with immediate gastric lavage. Intravenous
fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic
monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if
required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have
taken other drugs as well as SINEMET CR should be taken into consideration. To date, no experience
has been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant
proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are
expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of
800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of
carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a
significant proportion of mice are expected to die to 3360 mg/kg.
DOSAGE AND ADMINISTRATION
SINEMET CR contains carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100
tablet. The daily dosage of SINEMET CR must be determined by careful titration. Patients should be
monitored closely during the dose adjustment period, particularly with regard to appearance or worsening
of involuntary movements, dyskinesias or nausea. SINEMET CR should not be chewed or crushed.
Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be
used concomitantly while SINEMET CR is being administered, although their dosage may have to be
adjusted.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, SINEMET CR can be
given to patients receiving supplemental pyridoxine (vitamin B6).
Initial Dosage
Patients currently treated with conventional carbidopa levodopa preparations: Studies show that
peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and
greater. Because the bioavailabilities of carbidopa and levodopa in SINEMET and SINEMET CR are
different, appropriate adjustments should be made, as shown in Table 2.
Table 2: Approximate Bioavailabilities at Steady State*
Amount of
Approximate
Approximate Amount
Levodopa (mg)
Bioavailability
of Bioavailable
Tablet
in Each Tablet
Levodopa (mg) in
Each Tablet
SINEMET CR
50-200
200
0.70-0.75†
140-150
SINEMET
25-100
100
0.99‡
99
* This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the
bioavailability of carbidopa and levodopa.
† The extent of availability of levodopa from SINEMET CR was about 70-75% relative to intravenous levodopa or standard
SINEMET in the elderly.
‡ The extent of availability of levodopa from SINEMET was 99% relative to intravenous levodopa in the healthy elderly.
10
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage with SINEMET CR should be substituted at an amount that provides approximately 10% more
levodopa per day, although this may need to be increased to a dosage that provides up to 30% more
levodopa per day depending on clinical response (see DOSAGE AND ADMINISTRATION, Titration with
SINEMET CR). The interval between doses of SINEMET CR should be 4-8 hours during the waking day.
(See CLINICAL PHARMACOLOGY, Pharmacodynamics.)
A guideline for initiation of SINEMET CR is shown in Table 3.
Table 3: Guidelines for Initial Conversion from SINEMET to SINEMET CR
SINEMET
SINEMET CR
Total Daily Dose*
Suggested
Levodopa (mg)
Dosage Regimen
300-400
200 mg b.i.d.
500-600
300 mg b.i.d. or 200 mg t.i.d.
700-800
A total of 800 mg in 3 or more divided doses
(e.g., 300 mg a.m., 300 mg early p.m., and
200 mg later p.m.)
900-1000
A total of 1000 mg in 3 or more divided doses
(e.g., 400 mg a.m., 400 mg early p.m., and
200 mg later p.m.)
*For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION, Initial Dosage — Patients currently treated with
conventional carbidopa levodopa preparations.
Patients currently treated with levodopa without a decarboxylase inhibitor: Levodopa must be
discontinued at least twelve hours before therapy with SINEMET CR is started. SINEMET CR should be
substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In patients
with mild to moderate disease, the initial dose is usually 1 tablet of SINEMET CR 50-200 b.i.d.
Patients not receiving levodopa: In patients with mild to moderate disease, the initial recommended
dose is 1 tablet of SINEMET CR 50-200 b.i.d. Initial dosage should not be given at intervals of less than 6
hours.
Titration with SINEMET CR
Following initiation of therapy, doses and dosing intervals may be increased or decreased depending
upon therapeutic response. Most patients have been adequately treated with doses of SINEMET CR that
provide 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from 4 to
8 hours during the waking day. Higher doses of SINEMET CR (2400 mg or more of levodopa per day) and
shorter intervals (less than 4 hours) have been used, but are not usually recommended.
W hen doses of SINEMET CR are given at intervals of less than 4 hours, and/or if the divided doses
are not equal, it is recommended that the smaller doses be given at the end of the day.
An interval of at least 3 days between dosage adjustments is recommended.
Maintenance
Because Parkinson's disease is progressive, periodic clinical evaluations are recommended;
adjustment of the dosage regimen of SINEMET CR may be required.
Addition of Other Antiparkinson Medications
Anticholinergic agents, dopamine agonists, and amantadine can be given with SINEMET CR. Dosage
adjustment of SINEMET CR may be necessary when these agents are added.
A dose of carbidopa levodopa immediate release 25-100 or 10-100 (one half or a whole tablet) can be
added to the dosage regimen of SINEMET CR in selected patients with advanced disease who need
additional immediate-release levodopa for a brief time during daytime hours.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of SINEMET or SINEMET CR.
11
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be observed carefully if abrupt reduction or discontinuation of SINEMET CR is
required, especially if the patient is receiving neuroleptics. (See W ARNINGS.)
If general anesthesia is required, SINEMET CR may be continued as long as the patient is permitted to
take oral medication. If therapy is interrupted temporarily, the patient should be observed for symptoms
resembling NMS, and the usual dosage should be administered as soon as the patient is able to take oral
medication.
HOW SUPPLIED
No. 3919 — SINEMET CR 50-200 (carbidopa levodopa) Sustained-Release Tablets containing 50 mg
of carbidopa and 200 mg of levodopa, are dappled-purple in color, oval, compressed tablets, that are
coded “521” on one side and plain on the other. They are supplied as follows:
NDC 0006-3919-68 bottles of 100.
No. 3918 — SINEMET CR 25-100 (carbidopa levodopa) Sustained-Release Tablets containing 25 mg
of carbidopa and 100 mg of levodopa, are dappled-purple in color, oval, compressed tablets, that are
coded “601” on one side and plain on the other. They are supplied as follows:
NDC 0006-3918-68 bottles of 100.
Storage and Handling
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Store in a tightly closed container, protected from light and moisture.
Dispense in a tightly closed, light-resistant container.
Manufactured by:
Mylan Pharmaceuticals, Inc.
Morgantown, W V 26505, USA
Copyright 1996-2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 07/2014
uspi-mk0295b-txr-1406r003
Rx Only
12
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:09.623771
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019856s016s024s028lbl.pdf', 'application_number': 19856, 'submission_type': 'SUPPL ', 'submission_number': 28}
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11,785
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1
CIPRO® (ciprofloxacin hydrochloride) TABLETS
1
CIPRO® (ciprofloxacin) 5% and 10% ORAL SUSPENSION
2
3
PZXXXXXX
8/29/00
4
5
DESCRIPTION
6
CIPRO® (ciprofloxacin hydrochloride) Tablets and CIPRO® (ciprofloxacin) Oral
7
Suspension are synthetic broad spectrum antimicrobial agents for oral
8
administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the
9
monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-
10
(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow
11
crystalline substance with a molecular weight of 385.8. Its empirical formula is
12
C17H18FN3O3
lHCllH2O and its chemical structure is as follows:
13
14
[STRUCTURE]
15
16
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-
17
quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular
18
weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its
19
chemical structure is as follows:
20
21
[STRUCTURE]
22
23
Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-
24
position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-
25
position.
26
27
CIPRO® film-coated tablets are available in 100-mg, 250-mg, 500-mg and 750-mg
28
(ciprofloxacin equivalent) strengths. The inactive ingredients are starch,
29
microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate,
30
hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and water.
31
32
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and
33
10% (10 g ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a
34
white to slightly yellowish suspension with strawberry flavor which may contain
35
yellow-orange droplets. It is composed of ciprofloxacin microcapsules and diluent
36
which are mixed prior to dispensing (See instructions for USE/HANDLING). The
37
components of the suspension have the following compositions:
38
39
Microcapsules - ciprofloxacin, polyvinylpyrrolidone, methacrylic acid copolymer,
40
hydroxypropyl methylcellulose, magnesium stearate, and Polysorbate 20.
41
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
42
43
44
CLINICAL PHARMACOLOGY
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
46
Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the
47
gastrointestinal tract after oral administration. The absolute bioavailability is
48
approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin
49
maximum serum concentrations and area under the curve are shown in the chart for
50
the 250-mg to 1000-mg dose range.
51
52
Maximum
Area
53
Dose
Serum Concentration
Under Curve (AUC)
54
(mg)
(µµg/mL)
(µµg.hr/mL)
55
56
250
1.2
4.8
57
500
2.4
11.6
58
750
4.3
20.2
59
1000
5.4
30.8
60
61
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean
62
concentrations 12 hours after dosing with 250, 500, or 750-mg are 0.1, 0.2, and 0.4
63
mg/mL, respectively. Serum concentrations increase proportionately with doses up
64
to 1000-mg.
65
66
A 500-mg oral dose given every 12 hours has been shown to produce an area
67
under the serum concentration time curve (AUC) equivalent to that produced by an
68
intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.
69
A 750-mg oral dose given every 12 hours has been shown to produce an AUC at
70
steady-state equivalent to that produced by an intravenous infusion of 400 mg given
71
over 60 minutes every 8 hours. A 750-mg oral dose results in a Cmax similar to that
72
observed with a 400-mg I.V. dose. A 250-mg oral dose given every 12 hours
73
produces an AUC equivalent to that produced by an infusion of 200 mg
74
ciprofloxacin given every 12 hours.
75
76
Steady-state Pharmacokinetic Parameter
77
Following Multiple Oral and I.V. Doses
78
79
Parameters 500 mg
400 mg
750 mg
400 mg
80
q12h, P.O.
q12h, I.V. q12h, P.O.
q8h, I.V.
81
82
AUC (µglhr/mL) 13.7a
12.7a 31.6b 32.9c
83
Cmax(µg/mL
2.97
4.56 3.59
4.07
84
85
aAUC 0-12h bAUC 24h=AUC0-12hx2 cAUC 24h=AUC0-8hx3
86
87
88
89
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
The serum elimination half-life in subjects with normal renal function is approximately
90
4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the
91
urine as unchanged drug. After a 250-mg oral dose, urine concentrations of
92
ciprofloxacin usually exceed 200 µg/mL during the first two hours and are
93
approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion of
94
ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance
95
of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal
96
glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would
97
seem to play a significant role in its elimination. Co-administration of probenecid
98
with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal
99
clearance and a 50% increase in its concentration in the systemic circulation.
100
Although bile concentrations of ciprofloxacin are several fold higher than serum
101
concentrations after oral dosing, only a small amount of the dose administered is
102
recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is
103
recovered from the bile in the form of metabolites. Approximately 20 to 35% of an
104
oral dose is recovered from the feces within 5 days after dosing. This may arise
105
from either biliary clearance or transintestinal elimination. Four metabolites have
106
been identified in human urine which together account for approximately 15% of an
107
oral dose. The metabolites have antimicrobial activity, but are less active than
108
unchanged ciprofloxacin.
109
110
With oral administration, a 500-mg dose, given as 10 mL of the 5% CIPRO ®
111
Suspension (containing 250-mg ciprofloxacin/5mL) is bioequivalent to the 500-mg
112
tablet. A 10 mL volume of the 5% CIPRO ® Suspension (containing 250-mg
113
ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO ®
114
Suspension (containing 500-mg ciprofloxacin/5mL).
115
116
When CIPRO ® Tablet is given concomitantly with food, there is a delay in the
117
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours
118
after dosing rather than 1 hour whereas there is no delay observed when CIPRO ®
119
Suspension is given with food. The overall absorption of CIPRO ® Tablet or CIPRO
120
® Suspension, however, is not substantially affected. The pharmacokinetics of
121
ciprofloxacin given as the suspension are also not affected by food. Concurrent
122
administration of antacids containing magnesium hydroxide or aluminum hydroxide
123
may reduce the bioavailability of ciprofloxacin by as much as 90%. (See
124
PRECAUTIONS.)
125
126
The serum concentrations of ciprofloxacin and metronidazole were not altered when
127
these two drugs were given concomitantly.
128
129
Concomitant administration of ciprofloxacin with theophylline decreases the
130
clearance of theophylline resulting in elevated serum theophylline levels and
131
increased risk of a patient development CNS or other adverse reactions.
132
Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
133
paraxanthine after caffeine administration. (See PRECAUTIONS.)
134
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4
135
Pharmacokinetic studies of the oral (single dose) and intravenous (single and
136
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of
137
ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
138
adults. Although the Cmax is increased 16-40%, the increase in mean AUC is
139
approximately 30%, and can be at least partially attributed to decreased renal
140
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the
141
elderly. These differences are not considered clinically significant. (See
142
PRECAUTIONS: Geriatric Use.)
143
144
In patients with reduced renal function, the half-life of ciprofloxacin is slightly
145
prolonged. Dosage adjustments may be required. (See DOSAGE AND
146
ADMINISTRATION.)
147
148
In preliminary studies in patients with stable chronic liver cirrhosis, no significant
149
changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of
150
ciprofloxacin in patients with acute hepatic insufficiency, however, have not been
151
fully elucidated.
152
153
The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be
154
high enough to cause significant protein binding interactions with other drugs.
155
156
After oral administration, ciprofloxacin is widely distributed throughout the body.
157
Tissue concentrations often exceed serum concentrations in both men and women,
158
particularly in genital tissue including the prostate. Ciprofloxacin is present in active
159
form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum,
160
skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
161
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug
162
diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are
163
generally less than 10% of peak serum concentrations. Low levels of the drug have
164
been detected in the aqueous and vitreous humors of the eye.
165
166
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-
167
negative and gram-positive organisms. The bactericidal action of ciprofloxacin
168
results from interference with the enzyme DNA gyrase which is needed for the
169
synthesis of bacterial DNA. Ciprofloxacin does not cross-react with other
170
antimicrobial agents such as beta-lactams or aminoglycosides; therefore,
171
organisms resistant to these drugs may be susceptible to ciprofloxacin. In vitro
172
studies have shown that additive activity often results when ciprofloxacin is
173
combined with other antimicrobial agents such as beta-lactams, aminoglycosides,
174
clindamycin, or metronidazole. Synergy has been reported particularly with the
175
combination of ciprofloxacin and a beta-lactam; antagonism is observed only rarely.
176
177
Ciprofloxacin has been shown to be active against most strains of the following
178
microorganisms, both in vitro and in clinical infections as described in the
179
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
INDICATIONS AND USAGE section of the package insert for CIPRO®
180
(ciprofloxacin hydrochloride) Tablets and CIPRO® (ciprofloxacin) 5% and 10% Oral
181
Suspension.
182
183
Aerobic gram-positive microorganisms
184
Enterococcus faecalis (Many strains are only moderately susceptible.)
185
Staphylococcus aureus (methicillin susceptible)
186
Staphylococcus epidermidis
187
Staphylococcus saprophyticus
188
Streptococcus pneumoniae
189
Streptococcus pyogenes
190
191
192
Aerobic gram-negative microorganisms
193
Campylobacter jejuni
Proteus mirabilis
194
Citrobacter diversus
Proteus vulgaris
195
Citrobacter freundii
Providencia rettgeri
196
Enterobacter cloacae
Providencia stuartii
197
Escherichia coli
Pseudomonas aeruginosa
198
Haemophilus influenzae
Salmonella typhi
199
Haemophilus parainfluenzae
Serratia marcescens
200
Klebsiella pneumoniae
Shigella boydii
201
Moraxella catarrhalis
Shigella dysenteriae
202
Morganella morganii
Shigella flexneri
203
Neisseria gonorrhoeae
Shigella sonnei
204
205
206
Ciprofloxacin has been shown to be active against most strains of the following
207
microorganisms, both in vitro and in clinical infections as described in the
208
INDICATIONS AND USAGE section of the package insert for CIPRO® I.V.
209
(ciprofloxacin for intravenous infusion).
210
211
Aerobic gram-positive microorganisms
212
Enterococcus faecalis (Many strains are only moderately susceptible.)
213
Staphylococcus aureus (methicillin susceptible)
214
Staphylococcus epidermidis
215
Staphylococcus saprophyticus
216
Streptococcus pneumoniae
217
Streptococcus pyogenes
218
219
Aerobic gram-negative microorganisms
220
Citrobacter diversus
Morganella morganii
221
Citrobacter freundii
Proteus mirabilis
222
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Enterobacter cloacae
Proteus vulgaris
223
Escherichia coli
Providencia rettgeri
224
Haemophilus influenzae
Providencia stuartii
225
Haemophilus parainfluenzae
Pseudomonas aeruginosa
226
Klebsiella pneumoniae
Serratia marcescens
227
228
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro
229
and by use of serum levels as a surrogate marker (see INDICATIONS AND
230
USAGE and INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
231
232
The following in vitro data are available, but their clinical significance is
233
unknown.
234
235
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL
236
or less against most (>90%) strains of the following microorganisms; however, the
237
safety and effectiveness of ciprofloxacin in treating clinical infections due to these
238
microorganisms have not been established in adequate and well-controlled clinical
239
trials.
240
241
Aerobic gram-positive microorganisms
242
Staphylococcus haemolyticus
243
Staphylococcus hominis
244
245
Aerobic gram-negative microorganisms
246
Acinetobacter Iwoffi
Pasteurella multocida
247
Aeromonas hydrophila
Salmonella enteritidis
248
Edwardsiella tarda
Vibrio cholerae
249
Enterobacter aerogenes
Vibrio parahaemolyticus
250
Klebsiella oxytoca
Vibrio vulnificus
251
Legionella pneumophila
Yersinia enterocolitica
252
253
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas
254
maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including
255
Bacteroides fragilis and Clostridium difficile.
256
257
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
258
little effect when tested in vitro. The minimal bactericidal concentration (MBC)
259
generally does not exceed the minimal inhibitory concentration (MIC) by more than a
260
factor of 2. Resistance to ciprofloxacin in vitro develops slowly (multiple-step
261
mutation).
262
263
Susceptibility Tests
264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Dilution Techniques: Quantitative methods are used to determine antimicrobial
265
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
266
susceptibility of bacteria to antimicrobial compounds. The MICs should be
267
determined using a standardized procedure. Standardized procedures are based
268
on a dilution method1 (broth or agar) or equivalent with standardized inoculum
269
concentrations and standardized concentrations of ciprofloxacin powder. The MIC
270
values should be interpreted according to the following criteria:
271
272
For testing aerobic microorganisms other than Haemophilus influenzae,
273
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
274
275
MIC (µµg/mL)
Interpretation
276
< 1
Susceptible (S)
277
2
Intermediate (I)
278
> 4
Resistant (R)
279
280
aThese interpretive standards are applicable only to broth microdilution
281
susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with
282
2-5% lysed horse blood.
283
284
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
285
286
MIC (µµg/mL) Interpretation
287
< 1
Susceptible (S)
288
289
b This interpretive standard is applicable only to broth microdilution susceptibility
290
tests with Haemophilus influenzae and Haemophilus parainfluenzae using
291
Haemophilus Test Medium¹.
292
293
The current absence of data on resistant strains precludes defining any results other
294
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible “
295
category should be submitted to a reference laboratory for further testing.
296
297
For testing Neisseria gonorrhoeae
c:
298
299
MIC (µµg/mL) Interpretation
300
< 0.06
Susceptible (S)
301
302
c This interpretive standard is applicable only to agar dilution test with GC agar base
303
and 1% defined growth supplement.
304
305
The current absence of data on resistant strains precludes defining any results other
306
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible”
307
category should be submitted to a reference laboratory for further testing.
308
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8
309
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
310
antimicrobial compound in the blood reaches the concentrations usually achievable.
311
A report of “Intermediate” indicates that the result should be considered equivocal,
312
and, if the microorganism is not fully susceptible to alternative, clinically feasible
313
drugs, the test should be repeated. This category implies possible clinical
314
applicability in body sites where the drug is physiologically concentrated or in
315
situations where high dosage of drug can be used. This category also provides a
316
buffer zone which prevents small uncontrolled technical factors from causing major
317
discrepancies in interpretation. A report of “Resistant” indicates that the pathogen
318
is not likely to be inhibited if the antimicrobial compound in the blood reaches the
319
concentrations usually achievable; other therapy should be selected.
320
321
Standardized susceptibility test procedures require the use of laboratory control
322
microorganisms to control the technical aspects of the laboratory procedures.
323
Standard ciprofloxacin powder should provide the following MIC values:
324
325
Organism
MIC (µg/mL)
326
327
E. faecalis
ATCC 29212
0.25-2.0
328
E. coli
ATCC 25922
0.004-0.015
329
H. influenzae
a
ATCC 49247
0.004-0.03
330
N. gonorrhoeae
b
ATCC 49226
0.001-0.008
331
P. aeruginosa
ATCC 27853
0.25-1.0
332
S. aureus
ATCC 29213
0.12-0.5
333
334
a This quality control range is applicable to only H. influenzae ATCC 49247 tested
335
by a broth microdilution procedure using Haemophilus Test Medium (HTM)¹.
336
337
b This quality control range is applicable to only N. gonorrhoeae ATCC 49226
338
tested by an agar dilution procedure using GC agar base and 1% defined growth
339
supplement.
340
341
Diffusion Techniques: Quantitative methods that require measurement of zone
342
diameters also provide reproducible estimates of the susceptibility of bacteria to
343
antimicrobial compounds. One such standardized procedure2 requires the use
344
of standardized inoculum concentrations. This procedure uses paper disks
345
impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
346
ciprofloxacin.
347
348
Reports from the laboratory providing results of the standard single-disk
349
susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to
350
the following criteria:
351
352
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9
For testing aerobic microorganisms other than Haemophilus influenzae,
353
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
354
355
Zone Diameter (mm)
Interpretation
356
>21
Susceptible (S)
357
16-20
Intermediate (I)
358
<15
Resistant (R)
359
360
a These zone diameter standards are applicable only to tests performed for
361
streptococci using Mueller-Hinton agar supplemented with 5% sheep blood
362
incubated in 5% CO2.
363
364
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
365
366
Zone Diameter(mm)
Interpretation
367
21
Susceptible (S)
368
369
b This zone diameter standard is applicable only to tests with Haemophilus
370
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium
371
(HTM)
2.
372
373
The current absence of data on resistant strains precludes defining any results other
374
than “Susceptible”. Strains yielding zone diameter results suggestive of a
375
“nonsusceptible” category should be submitted to a reference laboratory for further
376
testing.
377
378
For testing Neisseria gonorrhoeae
c:
379
380
Zone Diameter (mm)
Interpretation
381
>36
Susceptible (S)
382
383
c This zone diameter standard is applicable only to disk diffusion tests with GC agar
384
base and 1% defined growth supplement.
385
386
The current absence of data on resistant strains precludes defining any results other
387
than “Susceptible”. Strains yielding zone diameter results suggestive of a
388
“nonsusceptible” category should be submitted to a reference laboratory for further
389
testing.
390
391
Interpretation should be as stated above for results using dilution techniques.
392
Interpretation involves correlation of the diameter obtained in the disk test with the
393
MIC for ciprofloxacin.
394
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
395
As with standardized dilution techniques, diffusion methods require the use of
396
laboratory control microorganisms that are used to control the technical aspects of
397
the laboratory procedures. For the diffusion technique, the 5-µg ciprofloxacin disk
398
should provide the following zone diameters in these laboratory test quality control
399
strains:
400
401
Organism
Zone Diameter (mm)
402
E. coli
ATCC 25922
30-40
403
H. influenzae
a
ATCC 49247
34-42
404
N. gonorrhoeae
b
ATCC 49226
48-58
405
P. aeruginosa
ATCC 27853
25-33
406
S. aureus
ATCC 25923
22-30
407
408
aThese quality control limits are applicable to only H. influenzae ATCC 49247
409
testing using Haemophilus Test Medium (HTM)².
410
411
b These quality control limits are applicable only to tests conducted with N.
412
gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and
413
1% defined growth supplement.
414
415
INDICATIONS AND USAGE
416
CIPRO® is indicated for the treatment of infections caused by susceptible strains of
417
the designated microorganisms in the conditions listed below. Please see
418
DOSAGE AND ADMINISTRATION for specific recommendations.
419
420
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae,
421
or Moraxella catarrhalis.
422
423
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella
424
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas
425
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or
426
Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute
427
exacerbations of chronic bronchitis.
428
429
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
430
the treatment of presumed or confirmed pneumonia secondary to Streptococcus
431
pneumoniae.
432
433
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
434
Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
435
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus
437
saprophyticus, or Enterococcus faecalis.
438
439
Acute Uncomplicated Cystitis in females caused by Escherichia coli or
440
Staphylococcus saprophyticus. (See DOSAGE AND ADMINSTRATION.)
441
442
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
443
444
Complicated Intra-Abdominal Infections (used in combination with
445
metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
446
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. (See DOSAGE AND
447
ADMINSTRATION.)
448
449
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella
450
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
451
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas
452
aeruginosa, Staphylococcus aureus (methicillin susceptible), Staphylococcus
453
epidermidis, or Streptococcus pyogenes.
454
455
Bone and Joint Infections caused by Enterobacter cloacae, Serratia
456
marcescens, or Pseudomonas aeruginosa.
457
458
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains),
459
Campylobacter jejuni, Shigella boydii*, Shigella dysenteriae, Shigella Flexneri or
460
Shigella sonnei
* when antibacterial therapy is indicated.
461
462
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
463
464
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier
465
state has not been demonstrated.
466
467
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
468
469
Inhalational anthrax (post-exposure): To reduce the incidence or progression of
470
disease following exposure to aerosolized Bacillus anthracis.
471
472
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate
473
endpoint reasonably likely to predict clinical benefit and provide the basis for this
474
indication.
4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
475
INFORMATION).
476
477
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
*Although treatment of infections due to this organism in this organ system
478
demonstrated a clinically significant outcome, efficacy was studied in fewer than 10
479
patients.
480
481
If anaerobic organisms are suspected of contributing to the infection, appropriate
482
therapy should be administered.
483
484
Appropriate culture and susceptibility tests should be performed before treatment in
485
order to isolate and identify organisms causing infection and to determine their
486
susceptibility to ciprofloxacin. Therapy with CIPRO® may be initiated before results
487
of these tests are known; once results become available appropriate therapy should
488
be continued. As with other drugs, some strains of Pseudomonas aeruginosa may
489
develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and
490
susceptibility testing performed periodically during therapy will provide information
491
not only on the therapeutic effect of the antimicrobial agent but also on the possible
492
emergence of bacterial resistance.
493
494
CONTRAINDICATIONS
495
CIPRO® (ciprofloxacin hydrochloride) is contraindicated in persons with a history of
496
hypersensitivity to ciprofloxacin or any member of the quinolone class of
497
antimicrobial agents.
498
499
WARNINGS
500
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC
501
PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), -
502
EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE),
503
PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN
504
ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and
505
Nursing Mothers subsections.) The oral administration of ciprofloxacin caused
506
lameness in immature dogs. Histopathological examination of the weight-bearing
507
joints of these dogs revealed permanent lesions of the cartilage. Related
508
quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
509
and other signs of arthropathy in immature animals of various species. (See
510
ANIMAL PHARMACOLOGY.)
511
512
Convulsions, increased intracranial pressure, and toxic psychosis have been
513
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may
514
also cause central nervous system (CNS) events including: dizziness, confusion,
515
tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
516
reactions may occur following the first dose. If these reactions occur in patients
517
receiving ciprofloxacin, the drug should be discontinued and appropriate measures
518
instituted. As with all quinolones, ciprofloxacin should be used with caution in
519
patients with known or suspected CNS disorders that may predispose to seizures
520
or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in
521
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
the presence of other risk factors that may predispose to seizures or lower the
522
seizure threshold (e.g. certain drug therapy, renal dysfunction). (See
523
PRECAUTIONS: General, Information for Patients, Drug Interactions and
524
ADVERSE REACTIONS.)
525
526
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
527
RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND
528
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status
529
epilepticus, and respiratory failure. Although similar serious adverse effects have
530
been reported in patients receiving theophylline alone, the possibility that these
531
reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant
532
use cannot be avoided, serum levels of theophylline should be monitored and
533
dosage adjustments made as appropriate.
534
535
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
536
following the first dose, have been reported in patients receiving quinolone therapy.
537
Some reactions were accompanied by cardiovascular collapse, loss of
538
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.
539
Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic
540
reactions require immediate emergency treatment with epinephrine. Oxygen,
541
intravenous steroids, and airway management, including intubation, should be
542
administered as indicated.
543
544
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia,
545
jaundice, and hepatic necrosis with fatal outcome have also been rarely reported in
546
patients receiving ciprofloxacin along with other drugs. The possibility that these
547
reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be
548
discontinued at the first appearance of a skin rash or any other sign of
549
hypersensitivity.
550
551
Pseudomembranous colitis has been reported with nearly all antibacterial
552
agents, including ciprofloxacin, and may range in severity from mild to life-
553
threatening. Therefore, it is important to consider this diagnosis in patients
554
who present with diarrhea subsequent to the administration of antibacterial
555
agents.
556
557
Treatment with antibacterial agents alters the normal flora of the colon and may
558
permit overgrowth of clostridia. Studies indicate that a toxin produced by
559
Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
560
561
After the diagnosis of pseudomembranous colitis has been established, therapeutic
562
measures should be initiated. Mild cases of pseudomembranous colitis usually
563
respond to drug discontinuation alone. In moderate to severe cases, consideration
564
should be given to management with fluids and electrolytes, protein
565
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
supplementation, and treatment with an antibacterial drug clinically effective against
566
C. difficile colitis.
567
568
Achilles and other tendon ruptures that required surgical repair or resulted in
569
prolonged disability have been reported with ciprofloxacin and other quinolones.
570
Ciprofloxacin should be discontinued if the patient experiences pain, inflammation,
571
or rupture of a tendon.
572
573
Ciprofloxacin has not been shown to be effective in the treatment of syphilis.
574
Antimicrobial agents used in high dose for short periods of time to treat gonorrhea
575
may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea
576
should have a serologic test for syphilis at the time of diagnosis. Patients treated
577
with ciprofloxacin should have a follow-up serologic test for syphilis after three
578
months.
579
580
PRECAUTIONS
581
General: Crystals of ciprofloxacin have been observed rarely in the urine of human
582
subjects but more frequently in the urine of laboratory animals, which is usually
583
alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin
584
has been reported only rarely in humans because human urine is usually acidic.
585
Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
586
should be well hydrated to prevent the formation of highly concentrated urine.
587
588
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
589
events, including: nervousness, agitation, insomnia, anxiety, nightmares or
590
paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)
591
592
Alteration of the dosage regimen is necessary for patients with impairment of renal
593
function. (See DOSAGE AND ADMINISTRATION.)
594
595
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction
596
has been observed in patients who are exposed to direct sunlight while receiving
597
some members of the quinolone class of drugs. Excessive sunlight should be
598
avoided. Therapy should be discontinued if phototoxicity occurs.
599
600
As with any potent drug, periodic assessment of organ system functions, including
601
renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
602
603
Information for Patients:
604
Patients should be advised:
605
♦ that ciprofloxacin may be taken with or without meals and to drink fluids liberally.
606
As with other quinolones, concurrent administration of ciprofloxacin with
607
magnesium/aluminum antacids, or sucralfate, Videx (didanosine)
608
chewable/buffered tablets or pediatric powder, or with other products containing
609
calcium, iron or zinc should be avoided. These products may be taken two
610
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
hours after or six hours before ciprofloxacin. Ciprofloxacin should not be taken
611
concurrently with milk or yogurt alone, since absorption of ciprofloxacin may be
612
significantly reduced. Dietary calcium as part of a meal, however, does not
613
significantly affect ciprofloxacin absorption
614
615
♦ that ciprofloxacin may be associated with hypersensitivity reactions, even
616
following a single dose, and to discontinue the drug at the first sign of a skin rash
617
or other allergic reaction.
618
619
♦ to avoid excessive sunlight or artificial ultraviolet light while receiving
620
ciprofloxacin and to discontinue therapy if phototoxicity occurs.
621
622
♦ to discontinue treatment; rest and refrain from exercise; and inform their
623
physician if they experience pain, inflammation, or rupture of a tendon.
624
625
♦ that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients
626
should know how they react to this drug before they operate an automobile or
627
machinery or engage in activities requiring mental alertness or coordination.
628
629
♦ that ciprofloxacin may increase the effects of theophylline and caffeine. There is
630
a possibility of caffeine accumulation when products containing caffeine are
631
consumed while taking quinolones.
632
633
♦ that convulsions have been reported in patients receiving quinolones, including
634
ciprofloxacin, and to notify their physician before taking this drug if there is a
635
history of this condition.
636
637
Drug Interactions: As with some other quinolones, concurrent administration of
638
ciprofloxacin with theophylline may lead to elevated serum concentrations of
639
theophylline and prolongation of its elimination half-life. This may result in increased
640
risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
641
use cannot be avoided, serum levels of theophylline should be monitored and
642
dosage adjustments made as appropriate.
643
644
Some quinolones, including ciprofloxacin, have also been shown to interfere with the
645
metabolism of caffeine. This may lead to reduced clearance of caffeine and a
646
prolongation of its serum half-life.
647
648
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent
649
cation-containing products such as magnesium/aluminum antacids, sucralfate,
650
Videx (didanosine) chewable/buffered tablets or pediatric powder, or products
651
containing calcium, iron, or zinc may substantially decrease its absorption, resulting
652
in serum and urine levels considerably lower than desired. (See DOSAGE AND
653
ADMINSTRATION for concurrent administration of these agents with ciprofloxacin.)
654
655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Histamine H2-receptor antagonists appear to have no significant effect on the
656
bioavailability of ciprofloxacin.
657
658
Altered serum levels of phenytoin (increased and decreased) have been reported in
659
patients receiving concomitant ciprofloxacin.
660
661
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has,
662
on rare occasions, resulted in severe hypoglycemia.
663
664
Some quinolones, including ciprofloxacin, have been associated with transient
665
elevations in serum creatinine in patients receiving cyclosporine concomitantly.
666
667
Quinolones have been reported to enhance the effects of the oral anticoagulant
668
warfarin or its derivatives. When these products are administered concomitantly,
669
prothrombin time or other suitable coagulation tests should be closely monitored.
670
671
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces
672
an increase in the level of ciprofloxacin in the serum. This should be considered
673
if patients are receiving both drugs concomitantly.
674
675
As with other broad spectrum antimicrobial agents, prolonged use of ciprofloxacin
676
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the
677
patient’s condition and microbial susceptibility testing is essential. If superinfection
678
occurs during therapy, appropriate measures should be taken.
679
680
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro
681
mutagenicity tests have been conducted with ciprofloxacin, and the test results are
682
listed below:
683
684
Salmonella/Microsome Test (Negative)
685
E. coli DNA Repair Assay (Negative)
686
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
687
Chinese Hamster V79 Cell HGPRT Test (Negative)
688
Syrian Hamster Embryo Cell Transformation Assay (Negative)
689
Saccharomyces cerevisiae Point Mutation Assay (Negative)
690
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion
691
Assay (Negative)
692
Rat Hepatocyte DNA Repair Assay (Positive)
693
694
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems
695
gave negative results:
696
697
Rat Hepatocyte DNA Repair Assay
698
Micronucleus Test (Mice)
699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Dominant Lethal Test (Mice)
700
701
Long-term carcinogenicity studies in mice and rats have been completed. After
702
daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up
703
to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or
704
tumorigenic effects in these species.
705
706
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not
707
reduce the time to appearance of UV-induced skin tumors as compared to vehicle
708
control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times
709
every two weeks for up to 78 weeks while concurrently being administered
710
ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
711
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal
712
to maximum recommended human dose based upon mg/m
2), as opposed to 34
713
weeks when animals were treated with both UVA and vehicle. The times to
714
development of skin tumors ranged from 16-32 weeks in mice treated concomitantly
715
with UVA and other quinolones.
3
716
717
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic
718
tumors. There are no data from similar models using pigmented mice and/or fully
719
haired mice. The clinical significance of these findings to humans is unknown.
720
721
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (0.8
722
times the highest recommended human dose of 1200 mg based upon body surface
723
area) revealed no evidence of impairment.
724
725
Pregnancy: Teratogenic Effects. Pregnancy Category C: Reproduction
726
studies have been performed in rats and mice using oral doses up to 100 mg/kg
727
(0.6 and 0.3 times the maximum daily human dose based upon body surface area,
728
respectively) and have revealed no evidence of harm to the fetus due to
729
ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced
730
gastrointestinal disturbances resulting in maternal weight loss and an increased
731
incidence of abortion, but no teratogenicity was observed at either dose. After
732
intravenous administration of doses up to 20 mg/kg, no maternal toxicity was
733
produced in the rabbit, and no embryotoxicity or teratogenicity was observed.
734
There are, however, no adequate and well-controlled studies in pregnant women.
735
Ciprofloxacin should be used during pregnancy only if the potential benefit justifies
736
the potential risk to the fetus. (See WARNINGS.)
737
738
Nursing Mothers: Ciprofloxacin is excreted in human milk. Because of the
739
potential for serious adverse reactions in infants nursing from mothers taking
740
ciprofloxacin, a decision should be made whether to discontinue nursing or to
741
discontinue the drug, taking into account the importance of the drug to the mother.
742
743
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Pediatric Use: Safety and effectiveness in pediatric patients and adolescents less
744
than 18 years of age have not been established, except for use in inhalational
745
anthrax (post-exposure). Ciprofloxacin causes arthropathy in juvenile animals. (See
746
WARNINGS.)
747
748
For the indication of inhalational anthrax (post-exposure), the risk-benefit
749
assessment indicates that administration of ciprofloxacin to pediatric patients is
750
appropriate. For information regarding pediatric dosing in inhalational anthrax
751
(post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
752
ANTHRAX – ADDITIONAL INFORMATION.
753
754
Short-term safety data from a single trial in pediatric cystic fibrosis patients are
755
available. In a randomized, double-blind clinical trial for the treatment of acute
756
pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients
757
received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by
758
ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
759
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and
760
tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 - 21 days. Patients less than 5
761
years of age were not studied. Safety monitoring in the study included periodic
762
range of motion examinations and gait assessments by treatment-blinded
763
examiners. Patients were followed for an average of 23 days after completing
764
treatment (range 0-93 days). This study was not designed to determine long term
765
effects and the safety of repeated exposure to ciprofloxacin.
766
767
In the study, injection site reactions were more common in the ciprofloxacin group
768
(24%) than in the comparison group (8%). Other adverse events were similar in
769
nature and frequency between treatment arms. Musculoskeletal adverse events
770
were reported in 22% of the patients in the ciprofloxacin group and 21% in the
771
comparison group. Decreased range of motion was reported in 12% of the
772
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia
773
was reported in 10% of the patients in the ciprofloxacin group and 11% in the
774
comparison group. One of sixty-seven patients developed arthritis of the knee nine
775
days after a ten day course of treatment with ciprofloxacin. Clinical symptoms
776
resolved, but an MRI showed knee effusion without other abnormalities eight months
777
after treatment. However, the relationship of this event to the patient’s course of
778
ciprofloxacin can not be definitively determined, particularly since patients with
779
cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease
780
process.
781
782
Geriatric Use : In a retrospective analysis of 23 multiple-dose controlled clinical
783
trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25%
784
of patients were greater than or equal to 65 years of age and 10% were greater
785
than or equal to 75 years of age. No overall differences in safety or effectiveness
786
were observed between these subjects and younger subjects, and other reported
787
clinical experience has not identified differences in responses between the elderly
788
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
and younger patients, but greater sensitivity of some older individuals on any drug
789
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by
790
the kidney, and the risk of adverse reactions may be greater in patients with
791
impaired renal function. No alteration of dosage is necessary for patients greater
792
than 65 years of age with normal renal function. However, since some older
793
individuals experience reduced renal function by virtue of their advanced age, care
794
should be taken in dose selection for elderly patients, and renal function monitoring
795
may be useful in these patients. (See CLINICAL PHARMACOLOGY and
796
DOSAGE AND ADMINISTRATION.)
797
798
ADVERSE REACTIONS
799
During clinical investigation with the tablet, 2,799 patients received 2,868 courses
800
of the drug. Adverse events that were considered likely to be drug related occurred
801
in 7.3% of patients treated, possibly related in 9.2% (total of 16.5% thought to be
802
possibly or probably related to drug therapy), and remotely related in 3.0%.
803
Ciprofloxacin was discontinued because of an adverse event in 3.5% of patients
804
treated, primarily involving the gastrointestinal system (1.5%), skin (0.6%), and
805
central nervous system (0.4%).
806
807
The most frequently reported events, drug related or not, were nausea (5.2%),
808
diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache
809
(1.2%), restlessness (1.1%), and rash (1.1%).
810
811
Additional events that occurred in less than 1% of ciprofloxacin patients are listed
812
below.
813
814
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope,
815
hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest,
816
cerebral thrombosis
817
CENTRAL NERVOUS SYSTEM: dizziness, lightheadedness, insomnia,
818
nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive
819
seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia,
820
depersonalization, depression, paresthesia (See above.) (See
821
PRECAUTIONS.)
822
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia,
823
intestinal perforation, gastrointestinal bleeding (See above.) Cholestatic
824
jaundice has been reported.
825
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or
826
chest pain, flare up of gout
827
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria,
828
urinary retention, urethral bleeding, vaginitis, acidosis
829
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
830
hemoptysis, bronchospasm, pulmonary embolism
831
SKIN/HYPERSENSITIVITY: pruritus, urticaria, photosensitivity, flushing, fever,
832
chills, angioedema, edema of the face, neck, lips, conjunctivae or hands,
833
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
cutaneous candidiasis, hyperpigmentation, erythema nodosum (See above.)
834
Allergic reactions ranging from urticaria to anaphylactic reactions have been
835
reported. (See WARNINGS.)
836
SPECIAL SENSES: blurred vision, disturbed vision (change in color
837
perception, overbrightness of lights), decreased visual acuity, diplopia, eye
838
pain, tinnitus, hearing loss, bad taste
839
840
Most of the adverse events reported were described as only mild or moderate in
841
severity, abated soon after the drug was discontinued, and required no treatment.
842
843
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged
844
by investigators to be related to elevated serum levels of theophylline possibly as a
845
result of drug interaction with ciprofloxacin.
846
847
In domestic clinical trials involving 214 patients receiving a single 250-mg oral dose,
848
approximately 5% of patients reported adverse experiences without reference to
849
drug relationship. The most common adverse experiences were vaginitis (2%),
850
headache (1%), and vaginal pruritus (1%). Additional reactions, occurring in 0.3%-
851
1% of patients, were abdominal discomfort, lymphadenopathy, foot pain, dizziness,
852
and breast pain. Less than 20% of these patients had laboratory values obtained,
853
and these results were generally consistent with the pattern noted for multi-dose
854
therapy.
855
856
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets
857
(500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500
858
mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a
859
CNS adverse event profile comparable to the control drugs.
860
861
Post-Marketing Adverse Events: Additional adverse events, regardless of
862
relationship to drug, reported from worldwide marketing experience with quinolones,
863
including ciprofloxacin, are:
864
BODY AS A WHOLE: change in serum phenytoin
865
CARDIOVASCULAR: postural hypotension, vasculitis
866
CENTRAL NERVOUS SYSTEM: agitation, confusion, delirium, dysphasia,
867
myoclonus, nystagmus, toxic psychosis
868
GASTROINTESTINAL: constipation, dyspepsia, flatulence, hepatic necrosis,
869
jaundice, pancreatitis, pseudomembranous colitis (The onset of
870
pseudomembranous colitis symptoms may occur during or after antimicrobial
871
treatment.)
872
HEMIC/LYMPHATIC: agranulocytosis, hemolytic anemia, methemoglobinemia,
873
prolongation of prothrombin time
874
METABOLIC/NUTRITIONAL: elevation of serum triglycerides, cholesterol,
875
blood glucose, serum potassium
876
MUSCULOSKELETAL: myalgia, possible exacerbation of myasthenia gravis,
877
tendinitis/tendon rupture
878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
RENAL/UROGENITAL: albuminuria, candiduria, renal calculi, vaginal
879
candidiasis
880
SKIN/HYPERSENSITIVITY: anaphylactic reactions, erythema
881
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal
882
necrolysis
883
SPECIAL SENSES: anosmia, taste loss (See PRECAUTIONS.)
884
885
Adverse Laboratory Changes: Changes in laboratory parameters listed as
886
adverse events without regard to drug relationship are listed below:
887
888
Hepatic -
Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%),
889
alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin
890
(0.3%).
891
Hematologic -
Eosinophilia (0.6%), leukopenia (0.4%), decreased blood
892
platelets (0.1%), elevated blood platelets (0.1%),
893
pancytopenia (0.1%).
894
Renal -
Elevations of serum creatinine (1.1%), BUN (0.9%),
895
CRYSTALLURIA, CYLINDRURIA, AND HEMATURIA HAVE
896
BEEN REPORTED.
897
898
Other changes occurring in less than 0.1% of courses were: elevation of serum
899
gammaglutamyl transferase, elevation of serum amylase, reduction in blood
900
glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis,
901
increase in blood monocytes, leukocytosis.
902
903
OVERDOSAGE
904
In the event of acute overdosage, the stomach should be emptied by inducing
905
vomiting or by gastric lavage. The patient should be carefully observed and given
906
supportive treatment. Adequate hydration must be maintained. Only a small
907
amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or
908
peritoneal dialysis.
909
910
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions
911
was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
912
913
Single doses of ciprofloxacin were relatively non-toxic via the oral route of
914
administration in mice, rats, and dogs. No deaths occurred within a 14-day post
915
treatment observation period at the highest oral doses tested; up to 5000 mg/kg in
916
either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed
917
included hypoactivity and cyanosis in both rodent species and severe vomiting in
918
dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500
919
mg/kg. Mortality was delayed in these animals, occurring 10-14 days after dosing.
920
921
DOSAGE AND ADMINSTRATION
922
923
The recommended adult dosage for acute sinusitis is 500-mg every 12 hours.
924
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
925
Lower respiratory tract infections may be treated with 500-mg every 12 hours. For
926
more severe or complicated infections, a dosage of 750-mg may be given every 12
927
hours.
928
929
Severe/complicated urinary tract infections or urinary tract infections caused by
930
organisms not highly susceptible to ciprofloxacin may be treated with 500-mg every
931
12 hours. For other mild/moderate urinary infections, the usual adult dosage is 250-
932
mg every 12 hours.
933
934
In acute uncomplicated cystitis in females, the usual dosage is 100-mg or 250-mg
935
every 12 hours. For acute uncomplicated cystitis in females, 3 days of treatment is
936
recommended while 7 to 14 days is suggested for other mild/moderate, severe or
937
complicated urinary tract infections.
938
939
The recommended adult dosage for chronic bacterial prostatitis is 500-mg every 12
940
hours.
941
942
The recommended adult dosage for oral sequential therapy of complicated intra-
943
abdominal infections is 500-mg every 12 hours. (To provide appropriate anaerobic
944
activity, metronidazole should be given according to product labeling.) (See
945
CIPRO® I.V. package insert.)
946
947
Skin and skin structure infections and bone and joint infections may be treated with
948
500-mg every 12 hours. For more severe or complicated infections, a dosage of
949
750-mg may be given every 12 hours.
950
951
The recommended adult dosage for infectious diarrhea or typhoid fever is 500-mg
952
every 12 hours. For the treatment of uncomplicated urethral and cervical
953
gonococcal infections, a single 250-mg dose is recommended.
954
955
See Instructions To The Pharmacist for Use/Handling of CIPRO® Oral
956
Suspension.
957
958
DOSAGE GUIDELINES
Infection Type or Severity Unit Dose Frequency Usual
Durations†
Acute Sinusitis
Mild/Moderate
500-mg
q 12 h
10 days
Lower Respiratory
Tract
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
7 to 14 days
7 to 14 days
Urinary Tract
Acute Uncomplicated
Mild/Moderate
Severe/Complicated
100-mg or 250-mg
250-mg
500-mg
q 12 h
q 12 h
q 12 h
3 Days
7 to 14 Days
7 to 14 Days
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Chronic Bacterial
Prostatitis
Mild/Moderate
500-mg
q 12 h
28 Days
Intra-Abdominal*
Complicated
500-mg
q 12 h
7 to 14 Days
Skin and Skin Structure
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
7 to 14 Days
7 to 14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
> 4 to 6 weeks
> 4 to 6 weeks
Infectious Diarrhea
Mild/Moderate/Severe
500-mg
q 12 h
5 to 7 Days
Typhoid Fever
Mild/Moderate
500-mg
q 12 h
10 Days
Urethral and Cervical
Gonococcal Infections
Uncomplicated
250-mg
single dose
single dose
Inhalational anthrax
(post-exposure)**
Adult
Pediatric
500-mg
15 mg/kg per
dose, not to
exceed 500-mg
per dose
q 12 h
q 12 h
60 Days
60 Days
* used in conjunction with metronidazole
959
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of
960
infection have disappeared, except for inhalational anthrax (post-exposure).
961
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
962
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in
963
humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
964
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
965
INFORMATION.
966
967
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250-mg of
968
ciprofloxacin.
969
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500-mg of
970
ciprofloxacin.
971
See Instructions for USE/HANDLING.
972
973
Volume (mL) of Oral Suspension
974
Dosage
5%
10%
975
250-mg
5 mL
2.5 mL
976
500-mg
10 mL
5 mL
977
750-mg
15 mL
7.5 mL
978
979
CIPRO (ciprofloxacin) 5% and 10% Oral Suspension should not be
980
administered through feeding tubes due to its physical characteristics.
981
982
Complicated Intra-Abdominal Infections: Sequential therapy [parenteral to oral -
983
400-mg CIPRO® IV q 12 h (plus IV metronidazole) è 500-mg CIPRO® Tablets q
984
12 h (plus oral metronidazole)] can be instituted at the discretion of the physician.
985
986
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
The determination of dosage for any particular patient must take into consideration
987
the severity and nature of the infection, the susceptibility of the causative organism,
988
the integrity of the patient’s host-defense mechanisms, and the status of renal
989
function and hepatic function.
990
991
The duration of treatment depends upon the severity of infection. Generally
992
ciprofloxacin should be continued for at least 2 days after the signs and symptoms
993
of infection have disappeared. The usual duration is 7 to 14 days; however, for
994
severe and complicated infections more prolonged therapy may be required. Bone
995
and joint infections may require treatment for 4 to 6 weeks or longer. Chronic
996
Bacterial Prostatitis should be treated for 28 days. Infectious diarrhea may be
997
treated for 5-7 days. Typhoid fever should be treated for 10 days.
998
999
Ciprofloxacin should be administered at least 2 hours before or 6 hours after
1000
magnesium/aluminum antacids, or sucralfate, Videx (Didanoside) chewable /
1001
buffereed tablets or pediatric powder for oral solution, or other products containg
1002
calcium, iron or zinc.
1003
1004
Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
1005
however, the drug is also metabolized and partially cleared through the biliary
1006
system of the liver and through the intestine. These alternate pathways of drug
1007
elimination appear to compensate for the reduced renal excretion in patients with
1008
renal impairment. Nonetheless, some modification of dosage is recommended,
1009
particularly for patients with severe renal dysfunction. The following table provides
1010
dosage guidelines for use in patients with renal impairment; however, monitoring of
1011
serum drug levels provides the most reliable basis for dosage adjustment:
1012
1013
RECOMMENDED STARTING AND MAINTENANCE DOSES
1014
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
1015
1016
Creatinine Clearance (mL/min)
Dose
1017
>50
See Usual Dosage.
1018
30 - 50
250-500 mg q 12 h
1019
5 - 29
250-500 mg q 18 h
1020
Patients on hemodialysis
250-500 mg q 24 h (after dialysis)
1021
or Peritoneal dialysis)
1022
1023
When only the serum creatinine concentration is known, the following formula may
1024
be used to estimate creatinine clearance.
1025
1026
Men: Creatinine clearance (mL/min) = Weight (kg) x (140-age)
1027
72 x serum creatinine (mg/dL)
1028
1029
Women: 0.85 x the value calculated for men.
1030
The serum creatinine should represent a steady state of renal function.
1031
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
1032
In patients with severe infections and severe renal impairment, a unit dose of 750-
1033
mg may be administered at the intervals noted above; however, patients should be
1034
carefully monitored and the serum ciprofloxacin concentration should be measured
1035
periodically. Peak concentrations (1-2 hours after dosing) should generally range
1036
from 2 to 4 µg/mL.
1037
1038
For patients with changing renal function or for patients with renal impairment and
1039
hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will
1040
provide additional guidance for adjusting dosage.
1041
1042
HOW SUPPLIED
1043
CIPRO® (ciprofloxacin hydrochloride) Tablets are available as round, slightly
1044
yellowish film-coated tablets containing 100-mg or 250-mg ciprofloxacin. The 100-
1045
mg tablet is coded with the word “CIPRO” on one side and “100” on the reverse
1046
side. The 250-mg tablet is coded with the word “CIPRO” on one side and “250” on
1047
the reverse side. CIPRO® is also available as capsule shaped, slightly yellowish
1048
film-coated tablets containing 500-mg or 750-mg ciprofloxacin. The 500-mg tablet
1049
is coded with the word “CIPRO” on one side and “500” on the reverse side. The
1050
750-mg tablet is coded with the word “CIPRO” on one side and “750” on the reverse
1051
side. CIPRO® 250-mg, 500-mg, and 750-mg are available in bottles of 50, 100,
1052
and Unit Dose packages of 100. The 100-mg strength is available only as CIPRO®
1053
Cystitis pack containing 6 tablets for use only in female patients with acute
1054
uncomplicated cystitis.
1055
1056
Strength
NDC Code
Tablet Identification
1057
1058
Bottles of 50:
750-mg
NDC 0026-8514-50 CIPRO 750
1059
Bottles of 100:
250-mg
NDC 0026-8512-51 CIPRO 250
1060
500-mg
NDC 0026-8513-51 CIPRO 500
1061
1062
Unit Dose
1063
Package of 100:
250-mg
NDC 0026-8512-48 CIPRO 250
1064
500-mg
NDC 0026-8513-48 CIPRO 500
1065
750-mg
NDC 0026-8514-48 CIPRO 750
1066
1067
Cystitis
1068
Package of 6:
100-mg
NDC 0026-8511-06
CIPRO 100
1069
1070
Store below 30°° C (86°° F).
1071
1072
CIPRO ® Oral Suspension is supplied in 5% (5g ciprofloxacin in 100 mL) and 10%
1073
(10g ciprofloxacin in 100 mL) strengths. The drug product is composed of two
1074
components (microcapsules and diluent) which are mixed prior to dispensing. See
1075
Instructions To The Pharmacist For Use/Handling.
1076
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
1077
1078
Total
Ciprofloxacin
Ciprofloxacin
1079
volume after
contents after
contents per
1080
reconstitution
reconstitution
bottle
NDC Code
1081
1082
100 mL
250 mg/5 mL
5,000 mg
0026-8551-36
1083
100 mL
500 mg/5 mL
10,000 mg
0026-8553-36
1084
1085
Microcapsules and diluent should be stored below 25°° C (77°° F) and
1086
protected from freezing.
1087
Reconstituted product may be stored below 30°° C (86°° F). Protect from
1088
freezing. A teaspoon is provided for the patient.
1089
1090
ANIMAL PHARMACOLOGY
1091
Ciprofloxacin and other quinolones have been shown to cause arthropathy in
1092
immature animals of most species tested. (See WARNINGS.) Damage of weight
1093
bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
1094
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the
1095
knee joint. At 30 mg/kg, the effect on the joint was minimal . In a subsequent study
1096
in beagles, removal of weight bearing from the joint reduced the lesions but did not
1097
totally prevent them.
1098
1099
Crystalluria, sometimes associated with secondary nephropathy, occurs in
1100
laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced
1101
solubility of ciprofloxacin under alkaline conditions, which predominate in the urine
1102
of test animals; in man, crystalluria is rare since human urine is typically acidic. In
1103
rhesus monkeys, crystalluria without nephropathy has been noted after single oral
1104
doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no
1105
nephropathological changes were noted; however, nephropathy was observed after
1106
dosing at 20 mg/kg/day for the same duration.
1107
1108
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid IV injection (15 sec.) produces
1109
pronounced hypotensive effects. These effects are considered to be related to
1110
histamine release, since they are partially antagonized by pyrilamine, an
1111
antihistamine. In rhesus monkeys, rapid IV injection also produces hypotension but
1112
the effect in this species is inconsistent and less pronounced.
1113
1114
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as
1115
phenylbutazone and indomethacin with quinolones has been reported to enhance
1116
the CNS stimulatory effect of quinolones.
1117
1118
Ocular toxicity seen with some related drugs has not been observed in
1119
ciprofloxacin-treated animals.
1120
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
1121
CLINICAL STUDIES
1122
Acute Sinusitis Studies
1123
Ciprofloxacin tablets (500-mg BID) were evaluated for the treatment of acute
1124
sinusitis in two randomized, double-blind, controlled clinical trials conducted in the
1125
United States. Study 1 compared ciprofloxacin with cefuroxime axetil (250-mg BID)
1126
and enrolled 501 patients (400 of whom were valid for the primary efficacy analysis).
1127
Study 2 compared ciprofloxacin with clarithromycin (500-mg BID) and enrolled 560
1128
patients (418 of whom were valid for the primary efficacy analysis). The primary test
1129
of cure endpoint was a follow-up visit performed approximately 30 days after the
1130
completion of treatment with study medication. Clinical response data from these
1131
studies are summarized below:
1132
1133
Drug Regimen
Clinical Response Resolution
1134
at 30 Day Follow-up n(%)
1135
STUDY 1
1136
CIPRO 500-mg
152/197 (77)
1137
BID x 10 days
1138
1139
Cefuroxime Axetil 250-mg
145/203 (71)
1140
BID x 10 days
1141
STUDY 2
1142
CIPRO 500-mg
168/212 (79)
1143
BID x 10 days
1144
1145
Clarithromycin 500-mg
169/206 (82)
1146
BID x 14 days
1147
1148
In ciprofloxacin-treated patients enrolled in controlled and uncontrolled acute
1149
sinusitis studies, all of which included antral puncture, bacteriological
1150
eradication/presumed eradication was documented at the 30 day follow-up visit in
1151
44 of 50 (88%) H. influenzae, 17 of 21 (80.9%) M. catarrhalis, and 42 of 51
1152
(82.3%) S. pneumoniae. Patients infected with S. pneumoniae strains whose
1153
baseline susceptibilities were intermediate or resistant to ciprofloxacin had a lower
1154
success rate than patients infected with susceptible strains.
1155
1156
Uncomplicated Cystitis Studies
1157
Efficacy: Two U.S. double-blind, controlled clinical studies of acute uncomplicated
1158
cystitis in women compared ciprofloxacin 100-mg BID for 3 days to ciprofloxacin
1159
250-mg BID for 7 days or control drug. In these two studies, using strict evaluability
1160
criteria and microbiologic and clinical response criteria at the 5-9 day post-therapy
1161
follow-up, the following clinical resolution and bacterial eradication rates were
1162
obtained:
1163
1164
Clinical Response
Bacteriological Response By
1165
Organism (Eradication Rate)
1166
1167
Drug Regimen
Resolution n(%)
E. coli n(%)
S. saprophyticus n(%)
1168
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
1169
STUDY 1
1170
CIPRO 100-mg
1171
BID x 3 days
82/94 (87)
64/70 (91)
8/8 (100)
1172
1173
CIPRO 250-mg
1174
BID x 7 days
81/86 (94)
67/69 (97)
4/4 (100)
1175
STUDY 2
1176
CIPRO 100-mg
1177
BID x 3 days
134/141 (95)
117/123 (95)
8/8 (100)
1178
1179
Control
128/133 (96)
103/105 (98)
10/10 (100)
1180
(3 days)
1181
1182
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
1183
1184
The mean serum concentrations of ciprofloxacin associated with a statistically
1185
significant improvement in survival in the rhesus monkey model of inhalational
1186
anthrax are reached or exceeded in adult and pediatric patients receiving oral and
1187
intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin
1188
pharmacokinetics have been evaluated in various human populations. The mean
1189
peak serum concentration achieved at steady state in human adults receiving 500
1190
mg orally every 12 hours is 2.97 µg/ml, and 4.56 µg/ml following 400 mg
1191
intravenously every 12 hours. The mean trough serum concentration at steady state
1192
for both of these regimens is 0.2 µg/ml. In a study of 10 pediatric patients between 6
1193
and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL
1194
and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute
1195
intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
1196
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a
1197
mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety
1198
data, including effects on cartilage, following the administration of ciprofloxacin to
1199
pediatric patients are limited. (For additional information, see PRECAUTIONS,
1200
Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
1201
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
1202
for this indication.
4
1203
1204
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
1205
dose of 11 LD50 (~5.5 x 105) spores (range 5-30 LD50) of B. anthracis was
1206
conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the
1207
anthrax strain used in this study was 0.08 µg/ml. In the animals studied, mean serum
1208
concentrations of ciprofloxacin achieved at expected Tmax
1209
(1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69
1210
µg/ml. Mean steady state trough concentrations at 12 hours post-dose ranged from
1211
0.12 to 0.19 µg/ml
5. Mortality due to anthrax for animals that received a 30-day
1212
regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly
1213
lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
1214
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug
1215
administration period.
6
1216
1217
Instructions To The Pharmacist For Use/Handling Of CIPRO® Oral
1218
Suspension:
1219
1220
Preparation of the suspension:
1221
1222
1223
[IMAGE]
1. The small bottle contains the microcapsules; the
1224
large bottle contains the diluent.
1225
1226
1227
[IMAGE]
2. Open both bottles. Child-proof cap: Press down
1228
according to instructions on the cap while turning to the
1229
left.
1230
1231
[IMAGE]
3. Pour the microcapsules completely into the large
1232
bottle of diluent. Do not add water to the
1233
suspension.
1234
1235
4. Remove the top layer of the diluent bottle label (to
1236
reveal the CIPRO ® Oral Suspension label).
1237
1238
[IMAGE]
5. Close the large bottle completely according to
1239
the directions on the cap and shake vigorously for
1240
about 15 seconds. The suspension is ready for use.
1241
1242
Instructions To The Patient For Taking CIPRO ® Oral Suspension:
1243
1244
Shake vigorously each time before use for approximately 15 seconds.
1245
1246
Swallow the prescribed amount of suspension. Do not chew the microcapsules.
1247
Reclose the bottle completely after use according to the instructions on the cap.
1248
Shake vigorously each time before use for approximately 15 seconds. The product
1249
can be used for 14 days when stored in a refrigerator or at room temperature
1250
(below 86°F). After treatment has been completed, any remaining suspension
1251
should not be reused.
1252
1253
1254
References: 1. National Committee for Clinical Laboratory Standards, Methods for
1255
Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth
1256
Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS,
1257
Wayne, PA, January 2000.
1258
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
2. National Committee for Clinical Laboratory Standards, Performance Standards
1259
for Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard
1260
NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
1261
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
1262
Product’s Advisory Committee meeting, March 31, 1993, Silver Spring MD. Report
1263
available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901
1264
Chapman Avenue, Room 200, Rockville, MD 20852, USA
1265
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-
1266
Threatening Illnesses)
1267
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
1268
during prolonged therapy in rhesus monkeys J Infect Dis 1992; 166: 1184-7.
1269
6. Friedlander AM, et al. Postexposure prophylaxis against experimental
1270
inhalational anthrax J Infect Dis 1993; 167: 1239-42.
1271
1272
1273
Rx Only
1274
PX###### 8/00 Bay o 9867 5202-2-A-U.S.-10
© 2000 Bayer Corporation XXXX
1275
CIPRO (R) (ciprofloxacin) 5% and 10% Oral Suspension Made in Italy. Printed in
1276
U.S.A.
1277
1278
1279
1280
1281
1282
1283
1284
1285
CIPRO® I.V.
1286
(ciprofloxacin)
1287
For Intravenous Infusion
1288
1289
PZXXXXXX
8/29/00
1290
DESCRIPTION
1291
1292
CIPRO® I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for
1293
intravenous (I.V.) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-
1294
6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical
1295
formula is C17H18FN3O3 and its chemical structure is:
1296
1297
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
N
O
F
N
HN
COOH
Ciprofloxacin
1298
1299
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of
1300
331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in
1301
water and ethanol. Ciprofloxacin differs from other quinolones in that it has a
1302
fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a
1303
cyclopropyl ring at the 1-position. CIPRO® I.V. solutions are available as sterile
1304
1.0% aqueous concentrates, which are intended for dilution prior to administration,
1305
and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
1306
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment.
1307
The pH range for the 1% aqueous concentrates in vials is 3.3 to 3.9. The pH range
1308
for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.
1309
1310
The plastic container is fabricated from a specially formulated polyvinyl chloride.
1311
Solutions in contact with the plastic container can leach out certain of its chemical
1312
components in very small amounts within the expiration period, e.g., di(2-ethylhexyl)
1313
phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has been
1314
confirmed in tests in animals according to USP biological tests for plastic
1315
containers as well as by tissue culture toxicity studies.
1316
1317
CLINICAL PHARMACOLOGY
1318
1319
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to
1320
normal volunteers, the mean maximum serum concentrations achieved were 2.1
1321
and 4.6 µg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2
1322
µg/mL, respectively.
1323
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
1324
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
1325
After 60-minute I.V. Infusions q 12 h.
1326
1327
Time after starting the infusion
1328
1329
Dose
30 min. 1 hr 3 hr 6 hr 8 hr 12 hr
1330
200 mg
1.7
2.1 0.6 0.3 0.2 0.1
1331
400 mg
3.7 4.6 1.3 0.7 0.5 0.2
1332
1333
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400
1334
mg administered intravenously. The serum elimination half-life is approximately 5-6
1335
hours and the total clearance is around 35 L/hr. Comparison of the
1336
pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen
1337
indicates no evidence of drug accumulation.
1338
1339
The absolute bioavailability of oral ciprofloxacin is within a range of 70-80% with no
1340
substantial loss by first pass metabolism. An intravenous infusion of 400 mg
1341
ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an
1342
area under the serum concentration time curve (AUC) equivalent to that produced
1343
by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg
1344
ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an
1345
AUC at steady-state equivalent to that produced by a 750-mg oral dose given every
1346
12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-
1347
mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an
1348
AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
1349
1350
Steady-state Pharmacokinetic Parameter
1351
Following Multiple Oral and I.V. Doses
1352
1353
Parameters 500 mg
400 mg
750 mg
400 mg
1354
q12h, P.O.
12h, I.V. q12h, P.O.
q8h, I.V.
1355
1356
AUC (µglhr/mL) 13.7a
12.7a 31.6b 32.9c
1357
Cmax(µg/mL) 2.97
4.56 3.59
4.07
1358
1359
aAUC 0-12h
bAUC 24h=AUC0-12hx2 cAUC 24h=AUC0-8hx3
1360
1361
After intravenous administration, approximately 50% to 70% of the dose is
1362
excreted in the urine as unchanged drug. Following a 200-mg I.V. dose,
1363
concentrations in the urine usually exceed 200 µg/mL 0-2 hours after dosing and are
1364
generally greater than 15 µg/mL 8-12 hours after dosing. Following a 400- mg I.V.
1365
dose, urine concentrations generally exceed 400 µg/mL 0-2 hours after dosing and
1366
are usually greater that 30 µg/mL 8-12 hours after dosing. The renal clearance is
1367
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by
1368
24 hours after dosing.
1369
1370
The serum concentrations of ciprofloxacin and metronidazole were not altered when
1371
these two drugs were given concomitantly.
1372
1373
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction
1374
in the ciprofloxacin renal clearance and a 50% increase in its concentration in the
1375
systemic circulation. Although bile concentrations of ciprofloxacin are several fold
1376
higher than serum concentrations after intravenous dosing, only a small amount of
1377
the administered dose (<1%) is recovered from the bile as unchanged drug.
1378
Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
1379
dosing.
1380
1381
After I.V. administration, three metabolites of ciprofloxacin have been identified in
1382
human urine which together account for approximately 10% of the intravenous dose.
1383
1384
Pharmacokinetic studies of the oral (single dose) and intravenous (single and
1385
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of
1386
ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
1387
adults. Although the Cmax is increased 16-40%, the increase in mean AUC is
1388
approximately 30%, and can be at least partially attributed to decreased renal
1389
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the
1390
elderly. These differences are not considered clinically significant. (See
1391
PRECAUTIONS: Geriatric Use.)
1392
1393
In patients with reduced renal function, the half-life of ciprofloxacin is slightly
1394
prolonged and dosage adjustments may be required. (See DOSAGE AND
1395
ADMINSTRATION.)
1396
1397
In preliminary studies in patients with stable chronic liver cirrhosis, no significant
1398
changes in ciprofloxacin pharmacokinetics have been observed. However, the
1399
kinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been
1400
fully elucidated.
1401
1402
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with
1403
50 mg/kg I.V. piperacillin sodium every four hours, mean serum ciprofloxacin
1404
concentrations were 3.02 µg/mL ½ hour and 1.18 µg/mL between 6-8 hours after
1405
the end of infusion.
1406
1407
The binding of ciprofloxacin to serum proteins is 20 to 40%.
1408
1409
After intravenous administration, ciprofloxacin is present in saliva, nasal and
1410
bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and
1411
prostatic secretions. It has also been detected in the lung, skin, fat, muscle,
1412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF
1413
concentrations are generally less than 10% of peak serum concentrations. Levels
1414
of the drug in the aqueous and vitreous chambers of the eye are lower than in
1415
serum.
1416
1417
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-
1418
negative and gram-positive microorganisms. The bactericidal action of
1419
ciprofloxacin results from interference with the enzyme DNA gyrase which is needed
1420
for the synthesis of bacterial DNA.
1421
1422
Ciprofloxacin has been shown to be active against most strains of the following
1423
microorganisms, both in vitro and in clinical infections as described in the
1424
INDICATIONS AND USAGE section of the package insert for CIPRO® I.V.
1425
(ciprofloxacin for intravenous infusion).
1426
1427
Aerobic gram-positive microorganisms
1428
Enterococcus faecalis (Many strains are only moderately susceptible.)
1429
Staphylococcus aureus (methicillin susceptible)
1430
Staphylococcus epidermidis
1431
Staphylococcus saprophyticus
1432
Streptococcus pneumoniae
1433
Streptococcus pyogenes
1434
1435
Aerobic gram-negative microorganisms
1436
Citrobacter diversus
Morganella morganii
1437
Citrobacter freundii
Proteus mirabilis
1438
Enterobacter cloacae
Proteus vulgaris
1439
Escherichia coli
Providencia rettgeri
1440
Haemophilus influenzae
Providencia stuartii
1441
Haemophilus parainfluenzae
Pseudomonas aeruginosa
1442
Klebsiella pneumoniae
Serratia marcescens
1443
Moraxella catarrhalis
1444
1445
Ciprofloxacin has been shown to be active against most strains of the following
1446
microorganisms, both in vitro and in clinical infections as described in the
1447
INDICATIONS AND USAGE section of the package insert for CIPRO®
1448
(ciprofloxacin hydrochloride) Tablets.
1449
1450
Aerobic gram-positive microorganisms
1451
1452
Enterococcus faecalis (Many strains are only moderately susceptible.)
1453
Staphylococcus aureus (methicillin susceptible)
1454
Staphylococcus epidermidis
1455
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Staphylococcus saprophyticus
1456
Streptococcus pneumoniae
1457
Streptococcus pyogenes
1458
1459
Aerobic gram-negative microorganisms
1460
Campylobacter jejuni
Proteus mirabilis
1461
Citrobacter diversus
Proteus vulgaris
1462
Citrobacter freundii
Providencia rettgeri
1463
Enterobacter cloacae
Providencia stuartii
1464
Escherichia coli
Pseudomonas aeruginosa
1465
Haemophilus influenzae
Salmonella typhi
1466
Haemophilus parainfluenzae
Serratia marcescens
1467
Klebsiella pneumoniae
Shigella boydii
1468
Moraxella catarrhalis
Shigella dysenteriae
1469
Morganella morganii
Shigella flexneri
1470
Neisseria gonorrhoeae
Shigella sonnei
1471
1472
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro
1473
and by use of serum levels as a surrogate marker (see INDICATIONS AND
1474
USAGE and INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
1475
1476
The following in vitro data are available, but their clinical significance is
1477
unknown.
1478
1479
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL
1480
or less against most (>90%) strains of the following microorganisms; however, the
1481
safety and effectiveness of ciprofloxacin in treating clinical infections due to these
1482
microorganisms have not been established in adequate and well-controlled clinical
1483
trials.
1484
1485
Aerobic gram-positive microorganisms
1486
Staphylococcus haemolyticus
1487
Staphylococcus hominis
1488
1489
Aerobic gram-negative microorganisms
1490
Acinetobacter Iwoffi
Pasteurella multocida
1491
Aeromonas hydrophila
Salmonella enteritidis
1492
Edwardsiella tarda
Vibrio cholerae
1493
Enterobacter aerogenes
Vibrio parahaemolyticus
1494
Klebsiella oxytoca
Vibrio vulnificus
1495
Legionella pneumophila
Yersinia enterocolitica
1496
1497
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas
1498
maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including
1499
Bacteroides fragilis and Clostridium difficile.
1500
1501
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
1502
little effect when tested in vitro. The minimum bactericidal concentration (MBC)
1503
generally does not exceed the minimum inhibitory concentration (MIC) by more than
1504
a factor of two. Resistance to ciprofloxacin in vitro usually develops slowly (multiple-
1505
step mutation).
1506
1507
Ciprofloxacin does not cross-react with other antimicrobial agents such as beta-
1508
lactams or aminoglycosides; therefore, organisms resistant to these drugs may be
1509
susceptible to ciprofloxacin.
1510
1511
In vitro studies have shown that additive activity often results when ciprofloxacin is
1512
combined with other antimicrobial agents such as beta-lactams, aminoglycosides,
1513
clindamycin, or metronidazole. Synergy has been reported particularly with the
1514
combination of ciprofloxacin and a beta-lactam; antagonism is observed only rarely.
1515
1516
Susceptibility Tests
1517
Dilution Techniques: Quantitative methods are used to determine antimicrobial
1518
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
1519
susceptibility of bacteria to antimicrobial compounds. The MICs should be
1520
determined using a standardized procedure. Standardized procedures are based
1521
on a dilution method1 (broth or agar) or equivalent with standardized inoculum
1522
concentrations and standardized concentrations of ciprofloxacin powder. The MIC
1523
values should be interpreted according to the following criteria:
1524
1525
For testing aerobic microorganisms other than Haemophilus influenzae,
1526
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
1527
1528
MIC (µµg/mL)
Interpretation
1529
< 1
Susceptible (S)
1530
2
Intermediate (I)
1531
> 4
Resistant (R)
1532
1533
aThese interpretive standards are applicable only to broth microdilution
1534
susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with
1535
2-5% lysed horse blood.
1536
1537
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
1538
1539
MIC (µµg/mL) Interpretation
1540
< 1
Susceptible (S)
1541
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
1542
b This interpretive standard is applicable only to broth microdilution susceptibility
1543
tests with Haemophilus influenzae and Haemophilus parainfluenzae using
1544
Haemophilus Test Medium¹.
1545
1546
The current absence of data on resistant strains precludes defining any results other
1547
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible “
1548
category should be submitted to a reference laboratory for further testing.
1549
1550
For testing Neisseria gonorrhoeae
c:
1551
1552
MIC (µµg/mL) Interpretation
1553
< 0.06
Susceptible (S)
1554
1555
c This interpretive standard is applicable only to agar dilution test with GC agar base
1556
and 1% defined growth supplement.
1557
1558
The current absence of data on resistant strains precludes defining any results other
1559
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible”
1560
category should be submitted to a reference laboratory for further testing.
1561
1562
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
1563
antimicrobial compound in the blood reaches the concentrations usually achievable.
1564
A report of “Intermediate” indicates that the result should be considered equivocal,
1565
and, if the microorganism is not fully susceptible to alternative, clinically feasible
1566
drugs, the test should be repeated. This category implies possible clinical
1567
applicability in body sites where the drug is physiologically concentrated or in
1568
situations where high dosage of drug can be used. This category also provides a
1569
buffer zone which prevents small uncontrolled technical factors from causing major
1570
discrepancies in interpretation. A report of “Resistant” indicates that the pathogen
1571
is not likely to be inhibited if the antimicrobial compound in the blood reaches the
1572
concentrations usually achievable; other therapy should be selected.
1573
1574
Standardized susceptibility test procedures require the use of laboratory control
1575
microorganisms to control the technical aspects of the laboratory procedures.
1576
Standard ciprofloxacin powder should provide the following MIC values:
1577
1578
Organism
MIC (µg/mL)
1579
1580
E. faecalis
ATCC 29212
0.25-2.0
1581
E. coli
ATCC 25922
0.004-0.015
1582
H. influenzae
a
ATCC 49247
0.004-0.03
1583
N. gonorrhoeae
b
ATCC 49226
0.001-0.008
1584
P. aeruginosa
ATCC 27853
0.25-1.0
1585
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
S. aureus
ATCC 29213
0.12-0.5
1586
1587
a This quality control range is applicable to only H. influenzae ATCC 49247 tested
1588
by a broth microdilution procedure using Haemophilus Test Medium (HTM)¹.
1589
1590
b This quality control range is applicable to only N. gonorrhoeae ATCC 49226
1591
tested by an agar dilution procedure using GC agar base and 1% defined growth
1592
supplement.
1593
1594
Diffusion Techniques: Quantitative methods that require measurement of zone
1595
diameters also provide reproducible estimates of the susceptibility of bacteria to
1596
antimicrobial compounds. One such standardized procedure2 requires the use
1597
of standardized inoculum concentrations. This procedure uses paper disks
1598
impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
1599
ciprofloxacin.
1600
1601
Reports from the laboratory providing results of the standard single-disk
1602
susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to
1603
the following criteria:
1604
1605
For testing aerobic microorganisms other than Haemophilus influenzae,
1606
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
1607
1608
Zone Diameter (mm)
Interpretation
1609
>21
Susceptible (S)
1610
16-20
Intermediate (I)
1611
<15
Resistant (R)
1612
1613
a These zone diameter standards are applicable only to tests performed for
1614
streptococci using Mueller-Hinton agar supplemented with 5% sheep blood
1615
incubated in 5% CO2.
1616
1617
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
1618
1619
Zone Diameter(mm)
Interpretation
1620
>21
Susceptible (S)
1621
1622
b This zone diameter standard is applicable only to tests with Haemophilus
1623
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium
1624
(HTM)
2.
1625
1626
The current absence of data on resistant strains precludes defining any results other
1627
than “Susceptible”. Strains yielding zone diameter results suggestive of a
1628
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
“nonsusceptible” category should be submitted to a reference laboratory for further
1629
testing.
1630
For testing Neisseria gonorrhoeae
c:
1631
1632
Zone Diameter (mm)
Interpretation
1633
>36
Susceptible (S)
1634
1635
c This zone diameter standard is applicable only to disk diffusion tests with GC agar
1636
base and 1% defined growth supplement.
1637
1638
The current absence of data on resistant strains precludes defining any results other
1639
than “Susceptible”. Strains yielding zone diameter results suggestive of a
1640
“nonsusceptible” category should be submitted to a reference laboratory for further
1641
testing.
1642
1643
Interpretation should be as stated above for results using dilution techniques.
1644
Interpretation involves correlation of the diameter obtained in the disk test with the
1645
MIC for ciprofloxacin.
1646
1647
As with standardized dilution techniques, diffusion methods require the use of
1648
laboratory control microorganisms that are used to control the technical aspects of
1649
the laboratory procedures. For the diffusion technique, the 5-µg ciprofloxacin disk
1650
should provide the following zone diameters in these laboratory test quality control
1651
strains:
1652
1653
Organism
Zone Diameter (mm)
1654
E. coli
ATCC 25922
30-40
1655
H. influenzae
a
ATCC 49247
34-42
1656
N. gonorrhoeae
b
ATCC 49226
48-58
1657
P. aeruginosa
ATCC 27853
25-33
1658
S. aureus
ATCC 25923
22-30
1659
1660
aThese quality control limits are applicable to only H. influenzae ATCC 49247
1661
testing using Haemophilus Test Medium (HTM)².
1662
1663
b These quality control limits are applicable only to tests conducted with N.
1664
gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and
1665
1% defined growth supplement.
1666
1667
INDICATIONS AND USAGE
1668
1669
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
CIPRO® I.V. is indicated for the treatment of infections caused by susceptible
1670
strains of the designated microorganisms in the conditions listed below when the
1671
intravenous administration offers a route of administration advantageous to the
1672
patient. Please see DOSAGE AND ADMINISTRATION for specific
1673
recommendations.
1674
1675
Urinary Tract Infections caused by Escherichia coli (including cases with
1676
secondary bacteremia), Klebsiella pneumoniae subspecies pneumoniae,
1677
Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
1678
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
1679
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus
1680
saprophyticus, or Enterococcus faecalis.
1681
1682
Lower Respiratory Infections caused by Escherichia coli, Klebsiella
1683
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis,
1684
Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus
1685
parainfluenzae, or Streptococcus pneumoniae.
1686
1687
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
1688
the treatment of presumed or confirmed pneumonia secondary to Streptococcus
1689
pneumoniae.
1690
1691
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella
1692
pneumoniae.
1693
1694
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella
1695
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis,
1696
Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii,
1697
Pseudomonas aeruginosa, Staphylococcus aureus (methicillin susceptible),
1698
Staphylococcus epidermidis, or Streptococcus pyogenes.
1699
1700
Bone and Joint Infections caused by Enterobacter cloacae, Serratia
1701
marcescens, or Pseudomonas aeruginosa.
1702
1703
Complicated Intra-Abdominal Infections (used in conjunction with
1704
metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
1705
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. (See DOSAGE AND
1706
ADMINSTRATION.)
1707
1708
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae,
1709
or Moraxella catarrhalis.
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
1711
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
1712
1713
Empirical Therapy for Febrile Neutropenic Patients in combination with
1714
piperacillin sodium. (See DOSAGE AND ADMINISTRATION and CLINICAL
1715
STUDIES.)
1716
1717
Inhalational anthrax (post-exposure): To reduce the incidence or progression of
1718
disease following exposure to aerosolized Bacillus anthracis.
1719
1720
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate
1721
endpoint reasonably likely to predict clinical benefit and provide the basis for this
1722
indication.
4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
1723
INFORMATION).
1724
1725
If anaerobic organisms are suspected of contributing to the infection, appropriate
1726
therapy should be administered.
1727
1728
Appropriate culture and susceptibility tests should be performed before treatment in
1729
order to isolate and identify organisms causing infection and to determine their
1730
susceptibility to ciprofloxacin. Therapy with CIPRO® I.V. may be initiated before
1731
results of these tests are known; once results become available, appropriate
1732
therapy should be continued.
1733
1734
As with other drugs, some strains of Pseudomonas aeruginosa may develop
1735
resistance fairly rapidly during treatment with ciprofloxacin. Culture and
1736
susceptibility testing performed periodically during therapy will provide information
1737
not only on the therapeutic effect of the antimicrobial agent but also on the possible
1738
emergence of bacterial resistance.
1739
1740
CLINICAL STUDIES
1741
1742
EMPIRICAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS
1743
1744
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with
1745
piperacillin sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile
1746
neutropenic patients were studied in one large pivotal multicenter, randomized trial
1747
and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with
1748
piperacillin sodium, 50 mg/kg I.V. q 4h.
1749
1750
The demographics of the evaluable patients were as follows:
1751
1752
Total
Ciprofloxacin/Piperacillin Tobramycin/Piperacillin
1753
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
N=233
N=237
1754
1755
Median Age (years)
47.0 (range 19-84)
50.0 (range 18-81)
1756
Male
114 (48.9%)
117 (49.4%)
1757
Female
119 (51.1%)
120 (50.6%)
1758
Leukemia/Bone Marrow
165 (70.8%)
158 (66.7%)
1759
Transplant
1760
Solid Tumor/Lymphoma
68 (29.2%)
79 (33.3%)
1761
Median Duration of
15.0 (range 1-61)
14.0 (range 1-89)
1762
Neutropenia (days)
1763
Clinical response rates observed in this study were as follows:
1764
1765
Outcomes
Ciprofloxacin/Piperacillin Tobramycin/Piperacillin
1766
N=233
N=237
1767
Success (%)
Success (%)
1768
1769
Clinical Resolution of
63 (27.0%)
52 (21.9%)
1770
Initial Febrile Episode with
1771
No Modifications of
1772
Empirical Regimen*
1773
1774
Clinical Resolution of
187 (80.3%)
185 (78.1%)
1775
Initial Febrile Episode
1776
Including Patients with
1777
Modifications of
1778
Empirical Regimen
1779
1780
Overall Survival 224 (96.1%)
223 (94.1%)
1781
1782
*To be evaluated as a clinical resolution, patients had to have: (1) resolution of
1783
fever; (2) microbiological eradication of infection (if an infection was
1784
microbiologically documented); (3) resolution of signs/symptoms of infection; and
1785
(4) no modification of empirical antibiotic regimen.
1786
1787
CONTRAINDICATIONS
1788
1789
CIPRO® I.V. (ciprofloxacin) is contraindicated in persons with history of
1790
hypersensitivity to ciprofloxacin or any member of the quinolone class of
1791
antimicrobial agents.
1792
1793
WARNINGS
1794
1795
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC
1796
PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), , -
1797
EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE),
1798
PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN
1799
ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and
1800
Nursing Mothers subsections.) Ciprofloxacin causes lameness in immature dogs.
1801
Histopathological examination of the weight-bearing joints of these dogs revealed
1802
permanent lesions of the cartilage. Related quinolone-class drugs also produce
1803
erosions of cartilage of weight-bearing joints and other signs of arthropathy in
1804
immature animals of various species. (See ANIMAL PHARMACOLOGY.)
1805
1806
Convulsions, increased intracranial pressure and toxic psychosis have been
1807
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may
1808
also cause central nervous system (CNS) events including: dizziness, confusion,
1809
tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
1810
reactions may occur following the first dose. If these reactions occur in patients
1811
receiving ciprofloxacin, the drug should be discontinued and appropriate measures
1812
instituted. As with all quinolones, ciprofloxacin should be used with caution in
1813
patients with known or suspected CNS disorders that may predispose to seizures
1814
or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in
1815
the presence of other risk factors that may predispose to seizures or lower the
1816
seizure threshold (e.g. certain drug therapy, renal dysfunction). (See
1817
PRECAUTIONS: General, Information for Patients, Drug Interaction and
1818
ADVERSE REACTIONS.)
1819
1820
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
1821
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
1822
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included
1823
cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar
1824
serious adverse events have been reported in patients receiving theophylline alone,
1825
the possibility that these reactions may be potentiated by ciprofloxacin cannot be
1826
eliminated. If concomitant use cannot be avoided, serum levels of theophylline
1827
should be monitored and dosage adjustments made as appropriate.
1828
1829
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
1830
following the first dose, have been reported in patients receiving quinolone therapy.
1831
Some reactions were accompanied by cardiovascular collapse, loss of
1832
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.
1833
Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic
1834
reactions require immediate emergency treatment with epinephrine and other
1835
resuscitation measures, including oxygen, intravenous fluids, intravenous
1836
antihistamines, corticosteroids, pressor amines, and airway management, as
1837
clinically indicated.
1838
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
1839
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia,
1840
jaundice, and hepatic necrosis with fatal outcome have also been reported
1841
extremely rarely in patients receiving ciprofloxacin along with other drugs. The
1842
possibility that these reactions were related to ciprofloxacin cannot be excluded.
1843
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
1844
other sign of hypersensitivity.
1845
1846
Pseudomembranous colitis has been reported with nearly all antibacterial
1847
agents, including ciprofloxacin, and may range in severity from mild to life-
1848
threatening. Therefore, it is important to consider this diagnosis in patients
1849
who present with diarrhea subsequent to the administration of antibacterial
1850
agents.
1851
1852
Treatment with antibacterial agents alters the normal flora of the colon and may
1853
permit overgrowth of clostridia. Studies indicate that a toxin produced by
1854
Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
1855
1856
After the diagnosis of pseudomembranous colitis has been established, therapeutic
1857
measures should be initiated. Mild cases of pseudomembranous colitis usually
1858
respond to drug discontinuation alone. In moderate to severe cases, consideration
1859
should be given to management with fluids and electrolytes, protein
1860
supplementation, and treatment with an antibacterial drug clinically effective against
1861
C. difficile colitis.
1862
1863
Achilles and other tendon ruptures that required surgical repair or resulted in
1864
prolonged disability have been reported with ciprofloxacin and other quinolones.
1865
Ciprofloxacin should be discontinued if the patient experiences pain, inflammation,
1866
or rupture of a tendon.
1867
1868
PRECAUTIONS
1869
1870
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINSTERED BY
1871
SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions
1872
have been reported with the intravenous administration of ciprofloxacin. These
1873
reactions are more frequent if infusion time is 30 minutes or less or if small veins of
1874
the hand are used. (See ADVERSE REACTIONS.)
1875
1876
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
1877
events, including: nervousness, agitation, insomnia, anxiety, nightmares or
1878
paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)
1879
1880
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects
1881
but more frequently in the urine of laboratory animals, which is usually alkaline. (See
1882
ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been
1883
reported only rarely in humans because human urine is usually acidic. Alkalinity of
1884
the urine should be avoided in patients receiving ciprofloxacin. Patients should be
1885
well hydrated to prevent the formation of highly concentrated urine.
1886
1887
Alteration of the dosage regimen is necessary for patients with impairment of renal
1888
function. (See DOSAGE AND ADMINSTRATION.)
1889
1890
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction
1891
has been observed in some patients who were exposed to direct sunlight while
1892
receiving some members of the quinolone class of drugs. Excessive sunlight
1893
should be avoided.
1894
1895
As with any potent drug, periodic assessment of organ system functions, including
1896
renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
1897
1898
Information For Patients: Patients should be advised that ciprofloxacin may be
1899
associated with hypersensitivity reactions, even following a single dose, and to
1900
discontinue the drug at the first sign of a skin rash or other allergic reaction.
1901
1902
Ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should
1903
know how they react to this drug before they operate an automobile or machinery or
1904
engage in activities requiring mental alertness or coordination.
1905
1906
Patients should be advised that ciprofloxacin may increase the effects of
1907
theophylline and caffeine. There is a possibility of caffeine accumulation when
1908
products containing caffeine are consumed while taking ciprofloxacin.
1909
1910
Patients should be advised to discontinue treatment; rest and refrain from exercise;
1911
and inform their physician if they experience pain, inflammation, or rupture of a
1912
tendon.
1913
1914
Patients should be advised that convulsions have been reported in patients taking
1915
quinolones, including ciprofloxacin, and to notify their physician before taking this
1916
drug if there is a history of this condition.
1917
1918
Drug Interactions: As with some other quinolones, concurrent administration of
1919
ciprofloxacin with theophylline may lead to elevated serum concentrations of
1920
theophylline and prolongation of its elimination half-life. This may result in increased
1921
risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
1922
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
use cannot be avoided, serum levels of theophylline should be monitored and
1923
dosage adjustments made as appropriate.
1924
1925
Some quinolones, including ciprofloxacin, have also been shown to interfere with the
1926
metabolism of caffeine. This may lead to reduced clearance of caffeine and
1927
prolongation of its serum half-life.
1928
1929
Some quinolones, including ciprofloxacin, have been associated with transient
1930
elevations in serum creatinine in patients receiving cyclosporine concomitantly.
1931
1932
Altered serum levels of phenytoin (increased and decreased) have been reported in
1933
patients receiving concomitant ciprofloxacin.
1934
1935
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has,
1936
in some patients, resulted in severe hypoglycemia. Fatalities have been reported.
1937
1938
Quinolones have been reported to enhance the effects of the oral anticoagulant
1939
warfarin or its derivatives. When these products are administered concomitantly,
1940
prothrombin time or other suitable coagulation tests should be closely monitored.
1941
1942
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an
1943
increase in the level of ciprofloxacin in the serum. This should be considered if
1944
patients are receiving both drugs concomitantly.
1945
1946
As with other broad-spectrum antimicrobial agents, prolonged use of ciprofloxacin
1947
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the
1948
patient’s condition and microbial susceptibility testing are essential. If
1949
superinfection occurs during therapy, appropriate measures should be taken.
1950
1951
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro
1952
mutagenicity tests have been conducted with ciprofloxacin. Test results are listed
1953
below:
1954
1955
Salmonella/Microsome Test (Negative)
1956
E. coli DNA Repair Assay (Negative)
1957
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
1958
Chinese Hamster V79 Cell HGPRT Test (Negative)
1959
Syrian Hamster Embryo Cell Transformation Assay (Negative)
1960
Saccharomyces cerevisiae Point Mutation Assay (Negative)
1961
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay
1962
(Negative)
1963
Rat Hepatocyte DNA Repair Assay (Positive)
1964
1965
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
Thus, two of the eight tests were positive, but results of the following three in vivo
1966
test systems gave negative results:
1967
1968
Rat Hepatocyte DNA Repair Assay
1969
Micronucleus Test (Mice)
1970
Dominant Lethal Test (Mice)
1971
1972
Long-term carcinogenicity studies in mice and rats have been completed. After
1973
daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up
1974
to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or
1975
tumorigenic effects in these species.
1976
1977
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not
1978
reduce the time to appearance of UV-induced skin tumors as compared to vehicle
1979
control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times
1980
every two weeks for up to 78 weeks while concurrently being administered
1981
ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
1982
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal
1983
to maximum recommended human dose based upon mg/m
2), as opposed to 34
1984
weeks when animals were treated with both UVA and vehicle. The times to
1985
development of skin tumors ranged from 16-32 weeks in mice treated concomitantly
1986
with UVA and other quinolones.
3
1987
1988
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic
1989
tumors. There are no data from similar models using pigmented mice and/or fully
1990
haired mice. The clinical significance of these findings to humans is unknown.
1991
1992
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (0.8
1993
times the highest recommended human dose of 1200 mg based upon body surface
1994
area) revealed no evidence of impairment.
1995
1996
Pregnancy: Teratogenic Effects. Pregnancy Category C: Reproduction
1997
studies have been performed in rats and mice using oral doses of up to 100mg/kg
1998
(0.8 and 0.4 times the maximum daily human dose based upon body surface area,
1999
respectively) and I.V. doses of up to 30 mg/kg (0.24 and 0.12 times the maximum
2000
daily human dose based upon body surface area, respectively) and have revealed
2001
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30
2002
and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal
2003
weight loss and an increased incidence of abortion, but no teratogenicity was
2004
observed at either dose. After intravenous administration of doses up to 20 mg/kg,
2005
no maternal toxicity was produced in the rabbit, and no embryotoxicity or
2006
teratogenicity was observed. There are, however, no adequate and well-controlled
2007
studies in pregnant women. Ciprofloxacin should be used during pregnancy only if
2008
the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)
2009
2010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Nursing Mothers: Ciprofloxacin is excreted in human milk. Because of the
2011
potential for serious adverse reactions in infants nursing from mothers taking
2012
ciprofloxacin, a decision should be made whether to discontinue nursing or to
2013
discontinue the drug, taking into account the importance of the drug to the mother.
2014
2015
Pediatric Use: Safety and effectiveness in pediatric patients and adolescents less
2016
than 18 years of age have not been established, except for use in inhalational
2017
anthrax (post-exposure). Ciprofloxacin causes arthropathy in juvenile animals. (See
2018
WARNINGS.)
2019
2020
For the indication of inhalational anthrax (post-exposure), the risk-benefit
2021
assessment indicates that administration of ciprofloxacin to pediatric patients is
2022
appropriate. For information regarding pediatric dosing in inhalational anthrax
2023
(post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
2024
ANTHRAX – ADDITIONAL INFORMATION.
2025
2026
Short-term safety data from a single trial in pediatric cystic fibrosis patients are
2027
available. In a randomized, double-blind clinical trial for the treatment of acute
2028
pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients
2029
received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by
2030
ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
2031
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and
2032
tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 - 21 days. Patients less than 5
2033
years of age were not studied. Safety monitoring in the study included periodic
2034
range of motion examinations and gait assessments by treatment-blinded
2035
examiners. Patients were followed for an average of 23 days after completing
2036
treatment (range 0-93 days). This study was not designed to determine long term
2037
effects and the safety of repeated exposure to ciprofloxacin.
2038
2039
In the study, injection site reactions were more common in the ciprofloxacin group
2040
(24%) than in the comparison group (8%). Other adverse events were similar in
2041
nature and frequency between treatment arms. Musculoskeletal adverse events
2042
were reported in 22% of the patients in the ciprofloxacin group and 21% in the
2043
comparison group. Decreased range of motion was reported in 12% of the
2044
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia
2045
was reported in 10% of the patients in the ciprofloxacin group and 11% in the
2046
comparison group. One of sixty-seven patients developed arthritis of the knee nine
2047
days after a ten day course of treatment with ciprofloxacin. Clinical symptoms
2048
resolved, but an MRI showed knee effusion without other abnormalities eight months
2049
after treatment. However, the relationship of this event to the patient’s course of
2050
ciprofloxacin can not be definitively determined, particularly since patients with
2051
cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease
2052
process.
2053
2054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical
2055
trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25%
2056
of patients were greater than or equal to 65 years of age and 10% were greater
2057
than or equal to 75 years of age. No overall differences in safety or effectiveness
2058
were observed between these subjects and younger subjects, and other reported
2059
clinical experience has not identified differences in responses between the elderly
2060
and younger patients, but greater sensitivity of some older individuals on any drug
2061
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by
2062
the kidney, and the risk of adverse reactions may be greater in patients with
2063
impaired renal function. No alteration of dosage is necessary for patients greater
2064
than 65 years of age with normal renal function. However, since some older
2065
individuals experience reduced renal function by virtue of their advanced age, care
2066
should be taken in dose selection for elderly patients, and renal function monitoring
2067
may be useful in these patients. (See CLINICAL PHARMACOLOGY and
2068
DOSAGE AND ADMINISTATION.)
2069
2070
ADVERSE REACTIONS
2071
2072
The most frequently reported events, without regard to drug relationship, among
2073
patients treated with intravenous ciprofloxacin were nausea, diarrhea, central
2074
nervous system disturbance, local I.V. site reactions, abnormalities of liver
2075
associated enzymes (hepatic enzymes), and eosinophilia. Headache,
2076
restlessness, and rash were also noted in greater than 1% of patients treated with
2077
the most common doses of ciprofloxacin.
2078
2079
Local I.V. site reactions have been reported with the intravenous administration of
2080
ciprofloxacin. These reactions are more frequent if the infusion time is 30 minutes
2081
or less. These may appear as local skin reactions which resolve rapidly upon
2082
completion of the infusion. Subsequent intravenous administration is not
2083
contraindicated unless the reactions recur or worsen.
2084
2085
Additional events, without regard to drug relationship or route of administration, that
2086
occurred in 1% or less of ciprofloxacin patients are listed below:
2087
2088
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest,
2089
myocardial infarction, arrhythmia, tachycardia, palpitation, cerebral
2090
thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina
2091
pectoris
2092
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic
2093
psychosis, depression, dysphasia, phobia, depersonalization, manic
2094
reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness,
2095
lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
2096
weakness, drowsiness, irritability, malaise, lethargy
2097
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile
2098
associated diarrhea, pseudomembranous colitis, pancreatitis, hepatic
2099
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
necrosis, intestinal perforation, dyspepsia, epigastric or abdominal pain,
2100
vomiting, constipation, oral ulceration, oral candidiasis, mouth dryness,
2101
anorexia, dysphagia, flatulence
2102
I.V. INFUSION SITE: thrombophlebitis, burning, pain, pruritus, paresthesia,
2103
erythema, swelling
2104
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck
2105
and chest pain, achiness, flare up of gout
2106
RENAL/UROGENITAL: renal failure, interstitial nephritis, hemorrhagic
2107
cystitis, renal calculi, frequent urination, acidosis, urethral bleeding, polyuria,
2108
urinary retention, gynecomastia, candiduria, vaginitis. Crystalluria,
2109
cylindruria, hematuria and albuminuria have also been reported.
2110
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea,
2111
pulmonary edema, respiratory distress, pleural effusion, hemoptysis,
2112
epistaxis, hiccough
2113
SKIN/HYPERSENSITIVITY: anaphylactic reactions, erythema
2114
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
2115
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck,
2116
conjunctivae, hands or lower extremities, purpura, fever, chills, flushing,
2117
pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration,
2118
hyperpigmentation, erythema nodosum, photosensitivity
2119
(See WARNINGS.)
2120
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision
2121
(flashing lights, change in color perception, overbrightness of lights,
2122
diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, a bad taste
2123
2124
Also reported were agranulocytosis, prolongation of prothrombin time, and
2125
possible exacerbation of myasthenia gravis.
2126
2127
Many of these events were described as only mild or moderate in severity,
2128
abated soon after the drug was discontinued, and required no treatment.
2129
2130
In several instances, nausea, vomiting, tremor, irritability, or palpitation were
2131
judged by investigators to be related to elevated serum levels of theophylline
2132
possibly as a result of drug interaction with ciprofloxacin.
2133
2134
In randomized, double-blind controlled clinical trials comparing ciprofloxacin
2135
(I.V. and I.V. P.O. sequential) with intravenous beta-lactam control antibiotics,
2136
the CNS adverse event profile of ciprofloxacin was comparable to that of the
2137
control drugs.
2138
2139
Post-Marketing Adverse Events: Additional adverse events, regardless of
2140
relationship to drug, reported from worldwide marketing experience with
2141
quinolones, including ciprofloxacin, are:
2142
2143
BODY AS A WHOLE: change in serum phenytoin
2144
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
CARDIOVASCULAR: postural hypotension, vasculitis
2145
CENTRAL NERVOUS SYSTEM: agitation, delirium,
2146
myoclonus, toxic psychosis
2147
HEMIC/LYMPHATIC: hemolytic anemia, methemoglobinemia
2148
METABOLIC/NUTRITIONAL: elevation of serum triglycerides,
2149
cholesterol, blood glucose, serum potassium
2150
MUSCULOSKELETAL: myalgia, tendinitis/tendon rupture
2151
RENAL/UROGENITAL: vaginal candidiasis
2152
(See PRECAUTIONS.)
2153
2154
Adverse Laboratory Changes: The most frequently reported changes in
2155
laboratory parameters with intravenous ciprofloxacin therapy, without regard to drug
2156
relationship are listed below:
2157
2158
Hepatic - elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase,
2159
LDH, and serum bilirubin;
2160
Hematologic - elevated eosinophil and platelet counts, decreased platelet
2161
counts, hemoglobin and/or hematocrit;
2162
Renal -
elevations of serum creatinine, BUN, and uric acid;
2163
Other -
elevations of serum creatinine phosphokinase, serum theophylline
2164
(in patients receiving theophylline concomitantly), blood glucose,
2165
and triglycerides.
2166
2167
Other changes occurring infrequently were: decreased leukocyte count, elevated
2168
atypical lymphocyte count, immature WBCs, elevated serum calcium, elevation of
2169
serum gamma-glutamyl transpeptidase (gamma GT), decreased BUN, decreased
2170
uric acid, decreased total serum protein, decreased serum albumin, decreased
2171
serum potassium, elevated serum potassium, elevated serum cholesterol.
2172
2173
Other changes occurring rarely during administration of ciprofloxacin were: elevation
2174
of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated
2175
sedimentation rate, change in serum phenytoin, decreased prothrombin time,
2176
hemolytic anemia, and bleeding diathesis.
2177
2178
OVERDOSAGE
2179
2180
In the event of acute overdosage, the patient should be carefully observed and given
2181
supportive treatment. Adequate hydration must be maintained. Only a small
2182
amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or
2183
peritoneal dialysis.
2184
2185
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions
2186
was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
2187
2188
DOSAGE AND ADMINSTRATION
2189
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
2190
The recommended adult dosage for urinary tract infections of mild to moderate
2191
severity is 200 mg I.V every 12 hours. For severe or complicated urinary tract
2192
infections, the recommended dosage is 400 mg I.V. every 12 hours.
2193
2194
The recommended adult dosage for lower respiratory tract infections, skin and skin
2195
structure infections, and bone and joint infections of mild to moderate severity is 400
2196
mg I.V. every 12 hours.
2197
2198
For severe/complicated infections of the lower respiratory tract, skin and skin
2199
structure, and bone and joint, the recommended adult dosage is 400 mg I.V. every 8
2200
hours.
2201
2202
The recommended adult dosage for mild, moderate, and severe nosocomial
2203
pneumonia is 400 mg I.V. every 8 hours.
2204
2205
Complicated Intra-Abdominal Infections: Sequential therapy [parenteral to oral -
2206
400 mg CIPRO® I.V. q12h (plus I.V. metronidazole) è 500 mg CIPRO® Tablets
2207
q12h (plus oral metronidazole)] can be instituted at the discretion of the physician.
2208
Metronidazole should be given according to product labeling to provide appropriate
2209
anaerobic coverage.
2210
2211
The recommended dosage for mild to moderate Acute Sinusitis and Chronic
2212
Bacterial Prostatitis is 400 mg I.V. every 12 hours.
2213
2214
The recommended adult dosage for empirical therapy of febrile neutropenic
2215
patients is 400 mg I.V. every 8 hours in combination with piperacillin sodium 50
2216
mg/kg I.V. q 4 hours, not to exceed 24 g/day (300 mg/kg/day), for 7-14 days.
2217
2218
The determination of dosage for any particular patient must take into consideration
2219
the severity and nature of the infection, the susceptibility of the causative
2220
microorganism, the integrity of the patient’s host-defense mechanisms, and the
2221
status of renal and hepatic function.
2222
2223
DOSAGE GUIDELINES
Intravenous
InfectionU
U
Type or Severity
Unit Dose
Frequency
Daily Dose
Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
400 mg
800 mg
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
1200 mg
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
Intra-Abdominal*
Complicated
400 mg
q12h
800 mg
Acute Sinusitis
Mild/Moderate
400 mg
q12h
800 mg
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
800 mg
Empirical Therapy in
Febrile Neutropenic
Patients
Severe
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
q8h
q4h
1200 mg
Not to exceed
24 g/day
Inhalational anthrax
(post-exposure) **
Adult
Pediatric
400 mg
10 mg/kg per dose, not
to exceed 400 mg per
dose
q12h
q12h
800 mg
Not to exceed 800
mg
* used in conjunction with metronidazole. (See product labeling for prescribing information.)
UDUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed
exposure. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans. For a discussion of ciprofloxacin serum concentrations in various human
populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION. Total duration of
ciprofloxacin administration (IV or oral) for inhalational anthrax (post-exposure) is 60 days.
2224
CIPRO® I.V. should be administered by intravenous infusion over a period
2225
of 60 minutes.
2226
2227
Parenteral drug products should be inspected visually for particulate matter and
2228
discoloration prior to administration.
2229
2230
Ciprofloxacin hydrochloride (CIPRO® Tablets) for oral administration are available.
2231
Parenteral therapy may be changed to oral CIPRO® Tablets when the condition
2232
warrants, at the discretion of the physician. For complete dosage and
2233
administration information, see CIPRO® Tablets package insert.
2234
2235
Impaired Renal Function: The following table provides dosage guidelines for use
2236
in patients with renal impairment; however, monitoring of serum drug levels provides
2237
the most reliable basis for dosage adjustment.
2238
2239
RECOMMENDED STARTING AND MAINTENANCE DOSES
2240
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
2241
2242
Creatinine Clearance (mL/min)
Dosage
2243
>30
See usual dosage.
2244
5-29
200-400 mg q 18-24 hr
2245
2246
When only the serum creatinine concentration is known, the following formula may
2247
be used to estimate creatinine clearance:
2248
2249
Men: Creatinine clearance (mL/min) = Weight (kg) x (140 - age)
2250
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
72 x serum creatinine (mg/dL)
2251
Women: 0.85 x the value calculated for men.
2252
2253
The serum creatinine should represent a steady state of renal function.
2254
2255
For patients with changing renal function or for patients with renal impairment and
2256
hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will
2257
provide additional guidance for adjusting dosage.
2258
2259
INTRAVENOUS ADMINISTRATION
2260
2261
CIPRO® I.V. should be administered by intravenous infusion over a period of 60
2262
minutes. Slow infusion of a dilute solution into a larger vein will minimize patient
2263
discomfort and reduce the risk of venous irritation.
2264
2265
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED
2266
BEFORE USE. The intravenous dose should be prepared by aseptically
2267
withdrawing the concentrate from the vial of CIPRO® I.V. This should be diluted with
2268
a suitable intravenous solution to a final concentration of 1-2mg/mL. (See
2269
COMPATIBILITY AND STABILITY.) The resulting solution should be infused over
2270
a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set
2271
which may already be in place.
2272
2273
If this method or the “piggyback” method of administration is used, it is advisable to
2274
discontinue temporarily the administration of any other solutions during the infusion
2275
of CIPRO® I.V.
2276
2277
Flexible Containers: CIPRO® I.V. is also available as a 0.2% premixed solution in
2278
5% dextrose in flexible containers of 100 mL or 200 mL. The solutions in flexible
2279
containers may be infused as described above.
2280
2281
COMPATIBILITY AND STABILITY
2282
2283
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous
2284
solutions to concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at
2285
refrigerated or room temperature storage.
2286
0.9% Sodium Chloride Injection, USP
2287
5% Dextrose Injection, USP
2288
Sterile Water for Injection
2289
10% Dextrose for Injection
2290
5% Dextrose and 0.225% Sodium Chloride for Injection
2291
5% Dextrose and 0.45% Sodium Chloride for Injection
2292
Lactated Ringer’s for Injection
2293
2294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
If CIPRO® I.V. is to be given concomitantly with another drug, each drug should be
2295
given separately in accordance with the recommended dosage and route of
2296
administration for each drug.
2297
2298
2299
HOW SUPPLIED
2300
2301
CIPRO® I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish
2302
solution. CIPRO® I.V. is available in 200 mg and 400 mg strengths. The
2303
concentrate is supplied in vials while the premixed solution is supplied in flexible
2304
containers as follows:
2305
2306
VIAL:
SIZE
STRENGTH
NDC NUMBER
2307
20 mL
200 mg, 1%
0026-8562-20
2308
40 mL
400 mg, 1%
0026-8564-64
2309
2310
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Abbott
2311
Laboratories, North Chicago, IL 60064.
2312
SIZE
STRENGTH
NDC NUMBER
2313
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
2314
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
2315
2316
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Baxter
2317
Healthcare Corporation, Deerfield, IL 60015.
2318
SIZE
STRENGTH
NDC NUMBER
2319
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
2320
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
2321
2322
STORAGE
2323
Vial:
Store between 5-30oC (41-86oF).
2324
Flexible Container:
Store between 5-25oC (41-77oF).
2325
2326
Protect from light, avoid excessive heat, protect from freezing.
2327
2328
CIPRO® I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
2329
2330
Ciprofloxacin is also available as CIPRO® (ciprofloxacin HCI) Tablets 100, 250,
2331
500, and 750 mg and CIPRO® (ciprofloxacin) 5% and 10% Oral Suspension.
2332
2333
ANIMAL PHARMACOLOGY
2334
2335
Ciprofloxacin and other quinolones have been shown to cause arthropathy in
2336
immature animals of most species tested. (See WARNINGS.) Damage of weight-
2337
bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
2338
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
ciprofloxacin given daily for 4 weeks caused degenerative articular changes of the
2339
knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study
2340
in beagles, removal of weight-bearing from the joint reduced the lesions but did not
2341
totally prevent them.
2342
2343
Crystalluria, sometimes associated with secondary nephropathy, occurs in
2344
laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced
2345
solubility of ciprofloxacin under alkaline conditions, which predominate in the urine
2346
of test animals; in man, crystalluria is rare since human urine is typically acidic. In
2347
rhesus monkeys, crystalluria without nephropathy has been noted after intravenous
2348
doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no
2349
nephropathological changes were noted; however, nephropathy was observed after
2350
dosing at 20 mg/kg/day for the same duration.
2351
2352
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection
2353
(15 sec.) produces pronounced hypotensive effects. These effects are considered
2354
to be related to histamine release because they are partially antagonized by
2355
pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also
2356
produces hypotension, but the effect in this species is inconsistent and less
2357
pronounced.
2358
2359
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as
2360
phenylbutazone and indomethacin, with quinolones has been reported to enhance
2361
the CNS stimulatory effect of quinolones.
2362
2363
Ocular toxicity, seen with some related drugs, has not been observed in
2364
ciprofloxacin-treated animals.
2365
2366
2367
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
2368
2369
The mean serum concentrations of ciprofloxacin associated with a statistically
2370
significant improvement in survival in the rhesus monkey model of inhalational
2371
anthrax are reached or exceeded in adult and pediatric patients receiving oral and
2372
intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin
2373
pharmacokinetics have been evaluated in various human populations. The mean
2374
peak serum concentration achieved at steady state in human adults receiving 500
2375
mg orally every 12 hours is 2.97 µg/ml, and 4.56 µg/ml following 400 mg
2376
intravenously every 12 hours. The mean trough serum concentration at steady state
2377
for both of these regimens is 0.2 µg/ml. In a study of 10 pediatric patients between 6
2378
and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL
2379
and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute
2380
intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
2381
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a
2382
mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety
2383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
data, including effects on cartilage, following the administration of ciprofloxacin to
2384
pediatric patients are limited. (For additional information, see PRECAUTIONS,
2385
Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
2386
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
2387
for this indication.
4
2388
2389
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
2390
dose of 11 LD50 (~5.5 x 105) spores (range 5-30 LD50) of B. anthracis was
2391
conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the
2392
anthrax strain used in this study was 0.08 µg/ml. In the animals studied, mean serum
2393
concentrations of ciprofloxacin achieved at expected Tmax
2394
(1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69
2395
µg/ml. Mean steady state trough concentrations at 12 hours post-dose ranged from
2396
0.12 to 0.19 µg/ml
5. Mortality due to anthrax for animals that received a 30-day
2397
regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly
2398
lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
2399
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug
2400
administration period.
6
2401
2402
References:
2403
1. National Committee for Clinical Laboratory Standards, Methods for Dilution
2404
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition.
2405
Approved Standard NCCLS Document M7- A5, Vol. 20, No. 2, NCCLS, Wayne,
2406
PA, January, 2000.
2407
2. National Committee for Clinical Laboratory Standards, Performance Standards
2408
for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard
2409
NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
2410
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
2411
Products Advisory Committee Meeting, March 31, 1993, Silver Spring MD. Report
2412
available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901
2413
Chapman Avenue, Room 200, Rockville, MD 20852, USA
2414
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-
2415
Threatening Illnesses)
2416
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
2417
during prolonged therapy in rhesus monkeys J Infect Dis 1992; 166: 1184-7.
2418
6. Friedlander AM, et al. Postexposure prophylaxis against experimental
2419
inhalational anthrax J Infect Dis 1993; 167: 1239-42.
2420
2421
2422
2423
Bayer Corporation
2424
Pharmaceutical Division
2425
400 Morgan Lane
2426
West Haven, CT 06516 USA
2427
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
2428
BAYER
2429
Rx Only
2430
2431
PZXXXXXX 8/00 BAY q 3939
5202-4-A-U.S.-7 ©2000 Bayer Corporation
2432
XXXX
2433
Printed in U.S.A.
2434
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:09.774892
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20780S08lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
11,787
|
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
08724752, R.6
4/04
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal
volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively;
the concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes
every 12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of
400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral
dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into
cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum
concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in
serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin
to serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200
µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing.
Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after
dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin
in patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-
dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-
hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less
than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5
years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5
µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within
the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children
is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately
60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin
and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin,
probenecid, and piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms
have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in situations
where high dosage of drug can be used. This category also provides a buffer zone, which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant”
indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood
reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test
with a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate
(I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than
“Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should
be submitted to a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or
Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for
the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae
subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa,
Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably
likely to predict clinical benefit and provide the basis for this indication.4 (See also,
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate
and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO I.V. may be initiated before results of these tests are known; once results become
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available, appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to
ciprofloxacin or any member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature
dogs. Histopathological examination of the weight-bearing joints of these dogs revealed
permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of
cartilage of weight-bearing joints and other signs of arthropathy in immature animals of
various species. (See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
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ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous
antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin
cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-
threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should
be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone.
In moderate to severe cases, consideration should be given to management with fluids and
electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective
against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may
be increased in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin
should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients
should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has
been excluded. Tendon rupture can occur during or after therapy with quinolones, including
ciprofloxacin.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
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the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is
30 minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of
the quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
•that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses
or not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not
be treatable by CIPRO I.V. or other antibacterial drugs in the future.
•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, they should discontinue treatment and contact their physicians.
•to discontinue treatment; rest and refrain from exercise; and inform their physician if they
experience pain, inflammation, or rupture of a tendon.
•that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
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•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18
years of age). Parents should inform their child’s physician if the child has a history of
joint-related problems before taking this drug. Parents of pediatric patients should also
notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and
ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some
patients, resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the
level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
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Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
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studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate
the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg
(0.6 and 0.3 times the maximum daily human dose based upon body surface area,
respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In
rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times
the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal
toxicity resulting in maternal weight loss and an increased incidence of abortion, but no
teratogenicity was observed at either dose level. After intravenous administration of doses up
to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon
mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was
observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed
by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants
nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-
exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is
not a drug of first choice in the pediatric population due to an increased incidence of adverse
events compared to the controls, including those related to joints and/or surrounding tissues.
The rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events
regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
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cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10
mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to
complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V.
50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients
less than 5 years of age were not studied. Safety monitoring in the study included periodic
range of motion examinations and gait assessments by treatment-blinded examiners. Patients
were followed for an average of 23 days after completing treatment (range 0-93 days). This
study was not designed to determine long term effects and the safety of repeated exposure to
ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an
MRI showed knee effusion without other abnormalities eight months after treatment.
However, the relationship of this event to the patient’s course of ciprofloxacin can not be
definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the
kidney, and the risk of adverse reactions may be greater in patients with impaired renal
function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal
function by virtue of their advanced age, care should be taken in dose selection for elderly
patients, and renal function monitoring may be useful in these patients. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events
reported were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an
adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
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system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or
moderate in severity, abated soon after the drug was discontinued, and required no treatment.
Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These
may appear as local skin reactions which resolve rapidly upon completion of the infusion.
Subsequent intravenous administration is not contraindicated unless the reactions recur or
worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac
murmur, hypertension, hypotension, angina pectoris, atrial flutter, ventricular ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis,
depression, dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia,
confusion, hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia,
nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal
convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC:
agranulocytosis,
prolongation
of
prothrombin
time,
lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest
pain, achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions,
erythema
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis,
angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever,
chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration,
hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia, erythema, swelling,
photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators
to be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
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In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally,
was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI)
or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The
trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa,
and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11
days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety within 6 weeks of therapy and through one year of
follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline
or treatment-emergent). These events were evaluated in a comprehensive fashion and
included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg
pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion
in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within
6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6.0 % (21/349) in comparator-treated patients. The
majority of these events were mild or moderate in intensity. All musculoskeletal events
occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30
days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients
than control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-
treated patients were more likely to report more than one event and on more than one
occasion compared to control patients. These events occurred in all age groups and the rates
were consistently higher in the ciprofloxacin group compared to the control group. At the end
of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335)
in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during
treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A
diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from
ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical
intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin
group versus 31% (109/349) in the comparator group. The most frequent events were
gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of
comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to
an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4%
(5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental
injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also
occur in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic
necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression
(life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia,
myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration
(serum),
potassium
elevation
(serum),
prothrombin
time
prolongation
or
decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or
after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-
Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis,
triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
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Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is
removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into
a larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See
Preparation of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human
populations,
see
INHALATIONAL
ANTHRAX
–
ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and
table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal
excretion; however, the drug is also metabolized and partially cleared through the biliary
system of the liver and through the intestine. These alternative pathways of drug elimination
appear to compensate for the reduced renal excretion in patients with renal impairment.
Nonetheless, some modification of dosage is recommended for patients with severe renal
dysfunction. The following table provides dosage guidelines for use in patients with renal
impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An
increased incidence of adverse events compared to controls, including events related to joints
and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial,
pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every
8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the
discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal
insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–
2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be
diluted and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL:
manufactured by Bayer HealthCare LLC and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Abbott
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin
(approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs)
given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric
dose based upon comparative plasma AUCs), no effects on joints were observed. This dose
was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
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and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-
dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for
animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-
treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for
treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was conducted in the US,
Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of
therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological
safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure
or TOC). The Per Protocol population had a causative organism(s) with protocol specified
colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs
for Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline,
and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for
clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after
prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology
information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
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NDA 19-847/SLR-028, SLR-029, SLR-031
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19847s028,029,031,19857s033,034,036lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 34}
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11,788
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
08724752, R.6
4/04
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal
volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively;
the concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a
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q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes
every 12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of
400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral
dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into
cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum
concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in
serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin
to serum proteins is 20 to 40%.
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200
µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing.
Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after
dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
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dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin
in patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-
dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-
hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less
than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5
years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5
µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within
the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children
is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately
60%.
Drug-drug Interactions: The potential for pharmacokinetic drug interactions between ciprofloxacin
and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin,
probenecid, and piperacillin sodium has been evaluated. (See PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
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package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms
have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
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Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzaea:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in situations
where high dosage of drug can be used. This category also provides a buffer zone, which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant”
indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood
reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
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reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test
with a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, and Haemophilus
parainfluenzae a:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate
(I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than
“Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should
be submitted to a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
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mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or
Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for
the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae
subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa,
Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella
catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably
likely to predict clinical benefit and provide the basis for this indication.4 (See also,
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate
and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO I.V. may be initiated before results of these tests are known; once results become
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For current labeling information, please visit https://www.fda.gov/drugsatfda
available, appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.
CONTRAINDICATIONS
CIPRO I.V. (ciprofloxacin) is contraindicated in persons with history of hypersensitivity to
ciprofloxacin or any member of the quinolone class of antimicrobial agents.
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature
dogs. Histopathological examination of the weight-bearing joints of these dogs revealed
permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of
cartilage of weight-bearing joints and other signs of arthropathy in immature animals of
various species. (See ANIMAL PHARMACOLOGY.)
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
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ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous
antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely in patients receiving
ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin
cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-
threatening. Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should
be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone.
In moderate to severe cases, consideration should be given to management with fluids and
electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective
against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may
be increased in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin
should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients
should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has
been excluded. Tendon rupture can occur during or after therapy with quinolones, including
ciprofloxacin.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
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the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is
30 minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of
the quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
•that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses
or not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not
be treatable by CIPRO I.V. or other antibacterial drugs in the future.
•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, they should discontinue treatment and contact their physicians.
•to discontinue treatment; rest and refrain from exercise; and inform their physician if they
experience pain, inflammation, or rupture of a tendon.
•that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18
years of age). Parents should inform their child’s physician if the child has a history of
joint-related problems before taking this drug. Parents of pediatric patients should also
notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and
ADVERSE REACTIONS.)
Drug Interactions: As with some other quinolones, concurrent administration of ciprofloxacin with
theophylline may lead to elevated serum concentrations of theophylline and prolongation of its
elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See
WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some
patients, resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the
level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
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Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
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studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate
the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg
(0.6 and 0.3 times the maximum daily human dose based upon body surface area,
respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In
rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times
the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal
toxicity resulting in maternal weight loss and an increased incidence of abortion, but no
teratogenicity was observed at either dose level. After intravenous administration of doses up
to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon
mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was
observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed
by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants
nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-
exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is
not a drug of first choice in the pediatric population due to an increased incidence of adverse
events compared to the controls, including those related to joints and/or surrounding tissues.
The rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events
regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
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For current labeling information, please visit https://www.fda.gov/drugsatfda
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10
mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to
complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V.
50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients
less than 5 years of age were not studied. Safety monitoring in the study included periodic
range of motion examinations and gait assessments by treatment-blinded examiners. Patients
were followed for an average of 23 days after completing treatment (range 0-93 days). This
study was not designed to determine long term effects and the safety of repeated exposure to
ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an
MRI showed knee effusion without other abnormalities eight months after treatment.
However, the relationship of this event to the patient’s course of ciprofloxacin can not be
definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the
kidney, and the risk of adverse reactions may be greater in patients with impaired renal
function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal
function by virtue of their advanced age, care should be taken in dose selection for elderly
patients, and renal function monitoring may be useful in these patients. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events
reported were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an
adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
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system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or
moderate in severity, abated soon after the drug was discontinued, and required no treatment.
Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These
may appear as local skin reactions which resolve rapidly upon completion of the infusion.
Subsequent intravenous administration is not contraindicated unless the reactions recur or
worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac
murmur, hypertension, hypotension, angina pectoris, atrial flutter, ventricular ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis,
depression, dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia,
confusion, hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia,
nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal
convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC:
agranulocytosis,
prolongation
of
prothrombin
time,
lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest
pain, achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions,
erythema
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis,
angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever,
chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration,
hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia, erythema, swelling,
photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators
to be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
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In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally,
was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI)
or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 + 4 years). The
trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa,
and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11
days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety within 6 weeks of therapy and through one year of
follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline
or treatment-emergent). These events were evaluated in a comprehensive fashion and
included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg
pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion
in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within
6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6.0 % (21/349) in comparator-treated patients. The
majority of these events were mild or moderate in intensity. All musculoskeletal events
occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30
days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients
than control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-
treated patients were more likely to report more than one event and on more than one
occasion compared to control patients. These events occurred in all age groups and the rates
were consistently higher in the ciprofloxacin group compared to the control group. At the end
of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335)
in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during
treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A
diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from
ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical
intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years <6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
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≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin
group versus 31% (109/349) in the comparator group. The most frequent events were
gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of
comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to
an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4%
(5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental
injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also
occur in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from worldwide
marketing experience with quinolones, including ciprofloxacin. Because these events are reported vol-
untarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, hepatic
necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression
(life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia,
myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration
(serum),
potassium
elevation
(serum),
prothrombin
time
prolongation
or
decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or
after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-
Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis,
triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
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Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is
removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into
a larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See
Preparation of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
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Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human
populations,
see
INHALATIONAL
ANTHRAX
–
ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and
table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal
excretion; however, the drug is also metabolized and partially cleared through the biliary
system of the liver and through the intestine. These alternative pathways of drug elimination
appear to compensate for the reduced renal excretion in patients with renal impairment.
Nonetheless, some modification of dosage is recommended for patients with severe renal
dysfunction. The following table provides dosage guidelines for use in patients with renal
impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
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Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An
increased incidence of adverse events compared to controls, including events related to joints
and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS and
CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial,
pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every
8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the
discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
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For current labeling information, please visit https://www.fda.gov/drugsatfda
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal
insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–
2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be
diluted and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL:
manufactured by Bayer HealthCare LLC and Hollister-Stier, Spokane, WA 99220.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0026-8562-20
40 mL
400 mg, 1%
0026-8564-64
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Abbott
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratories, North Chicago, IL 60064.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
CIPRO I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 100, 250, 500, and 750 mg and
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin
(approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs)
given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric
dose based upon comparative plasma AUCs), no effects on joints were observed. This dose
was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
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and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-
dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for
animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-
treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for
treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 + 4 years). The trial was conducted in the US,
Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of
therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological
safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure
or TOC). The Per Protocol population had a causative organism(s) with protocol specified
colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
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Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
PA, January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs
for Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline,
and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for
clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339. 9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after
prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology
information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516 USA
Rx Only
08724752, R.6
4/04
©2004 Bayer Pharmaceuticals Corporation
12318
58-7295
BAY q 3939
5202-4-A-U.S.-12
Printed In U.S.A.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-847/SLR-028, SLR-029, SLR-031
NDA 19-857/SLR-033, SLR-034, SLR-036
Page 9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:10.002425
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19847s028,029,031,19857s033,034,036lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
11,789
|
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
08938299, R.2
5/07
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO® I.V.
and other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
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The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg
administered intravenously. Comparison of the pharmacokinetic parameters following the 1st
and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no
substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin
given over 60 minutes every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every
12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8
hours has been shown to produce an AUC at steady-state equivalent to that produced by a
750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that
observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours
produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial
secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It
has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug
diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak
serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are
lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human
urine which together account for approximately 10% of the intravenous dose. The binding of
ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin
with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations
of these drugs and could lead to clinically significant adverse events of the coadministered drug
(see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35
L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in
the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually
exceed 200 µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours
after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL
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0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The
renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually
complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum
concentrations after intravenous dosing, only a small amount of the administered dose (< 1%)
is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered
from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in
patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
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ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
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Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
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the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with
a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
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As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus
pneumoniae, or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
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Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy
with CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline,
methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and
could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
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Other serious and sometimes fatal events, some due to hypersensitivity, and some due to
uncertain etiology, have been reported rarely in patients receiving therapy with quinolones,
including ciprofloxacin. These events may be severe and generally occur following the
administration of multiple doses. Clinical manifestations may include one or more of the
following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or
any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CIPRO, and may range in
severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after
the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased
in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be
discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest
and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
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PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has
been observed in some patients who were exposed to direct sunlight while receiving some members of the
quinolone class of drugs. Excessive sunlight should be avoided.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or
not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• to discontinue CIPRO treatment; rest and refrain from exercise; and inform their physician if they
experience pain, inflammation, or rupture of a tendon. The risk of serious tendon disorders with
quinolones is higher in those over 65 years of age, especially those on corticosteroids.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
• that diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can
develop watery and bloody stools (with or without stomach cramps and fever) even as late as
two or more months after having taken the last dose of the antibiotic. If this occurs, patients
should contact their physician as soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments
made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
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Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems
gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but
the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo-
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roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for
less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in
pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless
the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6
and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose
levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic
dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an
increased incidence of abortion, but no teratogenicity was observed at either dose level. After
intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no
embryotoxicity or teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure),
see DOSAGE
AND
ADMINISTRATION
and INHALATIONAL
ANTHRAX
–
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including those related to joints and/or surrounding tissues. The rates
of these events in pediatric patients with complicated urinary tract infection and pyelonephritis
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within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents.
The rates of these events occurring at any time up to the one year follow-up were 13.7%
(46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug
relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of
age were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical trials of
ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were
greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals on any drug
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney,
and the risk of adverse reactions may be greater in patients with impaired renal function. No
alteration of dosage is necessary for patients greater than 65 years of age with normal renal
function. However, since some older individuals experience reduced renal function by virtue of
their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
Patients over 65 years of age are at increased risk for developing severe tendon disorders
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including tendon rupture when being treated with a fluoroquinolone such as CIPRO. This risk
is further increased in patients receiving concomitant corticosteroid therapy. Tendon rupture
usually involves the Achilles, hand or shoulder tendons and can occur during therapy or up to a
few months post completion of therapy. Caution should be used when prescribing CIPRO to
elderly patients especially those on corticosteroids. Patients should be informed of this
potential side effect and advised to discontinue therapy and inform their physicians if any
tendon symptoms occur.
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported
were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V.
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as
local skin reactions which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
hypertension,
hypotension,
angina
pectoris,
atrial
flutter,
ventricular
ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
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RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions
including
life-threatening anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative
dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae,
hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning,
paresthesia, erythema, swelling, photosensitivity (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
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reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6.0%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Events: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these
events are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions
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to include these events in labeling are typically based on one or more of the following factors:
(1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection
to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative
dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia,
hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia,
moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy, phenytoin alteration (serum), potassium elevation (serum),
prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of
pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.),
psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste
loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell’s
Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See
PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also
INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
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OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION - ADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a
larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation
of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
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*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax (post-exposure) is
60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table
below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the
liver and through the intestine. These alternative pathways of drug elimination appear to
compensate for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended for patients with severe renal dysfunction. The
following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
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DOSAGE AND ADMINISTRATION - PEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased
incidence of adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
10-21 days*
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of
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1–2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: manufactured for Bayer Pharmaceuticals Corporation by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Hospira, Inc.,
Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: manufactured for Bayer Pharmaceuticals Corporation by Baxter
Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
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Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean
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peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects
on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In
the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean
steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5.
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin
beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group
(9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the
30-day drug administration period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
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Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
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The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests -
Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA,
January, 2000. 3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from
FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville,
MD 20852, USA. 4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for
Life-Threatening Illnesses). 5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and
ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 6.
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis
1993; 167: 1239-42. 7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians
(TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 8. Loebstein R, Addis
A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter
prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339. 9. Schaefer C,
Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a
case registry of the European network of teratology information services (ENTIS). Eur J Obstet
Gynecol Reprod Biol. 1996;69:83-89.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for:
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Distributed by:
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
Corporation.
Rx Only
08938299, R.2
5/07
©2007 Bayer Pharmaceuticals Corporation
13428
BAY q 3939
5202-4-A-U.S.-18
Printed In U.S.A.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:10.177929
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019857s46lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 46}
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
structural formula
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
Reference ID: 2910764
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CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
Reference ID: 2910764
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mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
Reference ID: 2910764
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MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Reference ID: 2910764
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Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate (I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
Reference ID: 2910764
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The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
provide the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
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The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
aeruginosa.
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Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
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Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If
these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and
appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in
patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction).
(See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
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fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
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Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
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Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
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malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
Reference ID: 2910764
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fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
Reference ID: 2910764
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
Reference ID: 2910764
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SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with flouroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
Reference ID: 2910764
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decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
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Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
7-14 Days
7-14 Days
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
≥ 4-6 Weeks
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
28 Days
Empirical Therapy
in
Severe
Febrile Neutropenic
Patients
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
Not to exceed
q8h
q4h
7-14 Days
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
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750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
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(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
Reference ID: 2910764
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5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V.
is available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Hospira, Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Baxter Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1759-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1782-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
Reference ID: 2910764
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PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Reference ID: 2910764
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Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial
Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000.
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
6. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
8. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® before you start taking it and each time you get a
refill. There may be new information. This Medication Guide does not take the place of talking to your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO can cause side effects that may
be serious or even cause death. If you get any of the following serious side effects, get medical help right
away. Talk with your healthcare provider about whether you should continue to take CIPRO.
• Tendon rupture or swelling of the tendon (tendinitis)
• Tendons are tough cords of tissue that connect muscles to bones.
• Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles),
shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone
antibiotics, including CIPRO. The risk of getting tendon problems is higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in
patients who take fluoroquinolones who do not have the above risk factors.
• Other reasons for tendon ruptures can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation.
Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by your healthcare provider.
Avoid exercise and using the affected area. The most common area of pain and swelling is the
Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your
healthcare provider about the risk of tendon rupture with continued use of CIPRO. You may need a
different antibiotic that is not a fluoroquinolone to treat your infection.
• Tendon rupture can happen while you are taking or after you have finished taking CIPRO. Tendon
ruptures have happened up to several months after patients have finished taking their
fluoroquinolone.
Reference ID: 2910764
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• Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
• Worsening of myasthenia gravis (a disease which causes muscle weakness). Fluoroquinolones
like CIPRO may cause worsening of myasthenia gravis symptoms, including muscle weakness and
breathing problems. Call your healthcare provider right away if you have any worsening muscle
weakness or breathing problems.
See the section “What are the possible side effects of CIPRO?” for more information about side
effects.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain germs
called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon
(musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be used as
the first choice of antibiotic medicine in children under 18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children under 18 years
old, except to treat specific serious infections, such as complicated urinary tract infections and to
prevent anthrax disease after breathing the anthrax bacteria germ (inhalational exposure). It is not
known if CIPRO XR is safe and works in children under 18 years of age.
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in
the sinuses and lungs, such as the common cold or flu. Antibiotics, including CIPRO, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are taking
CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
• have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic
to any of the ingredients in CIPRO. Ask your healthcare provider if you are not sure. See the list of
ingredients in CIPRO at the end of this Medication Guide.
• also take a medicine called tizanidine (Zanaflex®). Serious side effects from tizanidine are likely to
happen.
What should I tell my healthcare provider before taking CIPRO?
See “What is the most important information I should know about CIPRO?”
Tell your healthcare provider about all your medical conditions, including if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis)
• have central nervous system problems (such as epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other medicines
can affect each other causing side effects. Especially tell your healthcare provider if you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are
NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may increase your
risk of central nervous system effects and seizures. See "What are the possible side effects of
CIPRO?".
• a blood thinner (warfarin, Coumadin®, Jantoven®)
• tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine. See “Who
should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible side
effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended Phenytoin
Sodium®, Prompt Penytoin Sodium®, Phenytek®)
• products that contain caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the possible side
effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of
tendon injury. See “What is the most important information I should know about CIPRO?”
• methotrexate (Trexall®)
• Probenecid (Probalan®, Col-probenecid®)
• Metoclopromide (Reglan®, Reglan ODT®)
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from working correctly.
Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after taking these
products:
• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc
• sucralfate (Carafate®)
•
didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and
pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow the
tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day. Shake
the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to make sure the
suspension is mixed well. Close the bottle completely after use.
Reference ID: 2910764
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• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet whole. Do
not split, crush or chew the tablet. Tell your healthcare provider if you can not swallow the tablet
whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60 minutes,
as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you finish your
prescribed treatment, unless:
• you have tendon effects (see “What is the most important information I should know about
CIPRO?”),
• you have a serious allergic reaction (see “What are the possible side effects of CIPRO?”), or
•
your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will
become resistant to CIPRO. If this happens, CIPRO and other antibiotic medicines may not work in
the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember. Do not
take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than one dose
in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V. after
being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance of getting anthrax
disease or worsening of the disease after you are exposed to the anthrax bacteria germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking CIPRO without
talking with your healthcare provider. If you stop taking CIPRO too soon, it may not keep you from
getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or I.V. When taking
your CIPRO to prevent anthrax infection, you and your healthcare provider should talk about
whether the risks of stopping CIPRO too soon are more important than the risks of side effects with
CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your healthcare
provider should decide whether the benefits of taking CIPRO Tablets, Oral Suspension or I.V. for
anthrax are more important than the risks.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other
activities that require mental alertness or coordination until you know how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make your skin
sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get
severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking
CIPRO, call your healthcare provider right away. You should use a sunscreen and wear a hat and
clothes that cover your skin if you have to be in sunlight.
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the most
important information I should know about CIPRO?”
Other serious side effects of CIPRO include:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics including CIPRO. Tell
your healthcare provider if you have a history of seizures. Ask your healthcare provider whether
taking CIPRO will change your risk of having a seizure.
Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of
CIPRO. Talk to your healthcare provider right away if you get any of these side effects, or other
changes in mood or behavior:
• feel dizzy
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
• trouble sleeping
• nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even after only
one dose. Stop taking CIPRO and get emergency medical help right away if you get any of the
following symptoms of a severe allergic reaction:
• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right away if
you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can
be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking CIPRO at the
first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious
reaction to CIPRO.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular
heartbeat), or if you faint. CIPRO may cause a rare heart problem known as prolongation of the QT
interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of
this event are higher in people:
• who are elderly
Reference ID: 2910764
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• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody
stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or
more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones,
including CIPRO. Talk with your healthcare provider right away if you get any of the following
symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
• pain
• burning
• tingling
• numbness
•
weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes medicine
glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia)
which can sometimes be severe. Tell your healthcare provider if you get low blood sugar with
CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18 years old.
Tell your child’s healthcare provider if your child has any joint problems during or after treatment
with CIPRO.
The most common side effects of CIPRO include:
• nausea
• headache
• diarrhea
• vomiting
• vaginal yeast infection
• changes in liver function tests
•
pain or discomfort in the abdomen
These are not all the possible side effects of CIPRO. Tell your healthcare provider about any side effect
that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
Reference ID: 2910764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would like
more information about CIPRO, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about CIPRO that is written for healthcare professionals. For
more information go to www.CIPRO.com or call 1-800-526-4099.
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone,
magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20. Diluentmedium-chain triglycerides, sucrose,
lecithin, water, and strawberry flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH adjustment
Revised February 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for: company logo
Bayer HealthCare Pharmaceuticals Inc.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Wayne, NJ 07470
Manufactured in Germany
or
Manufactured in Norway
By Fresenius Kabi Norge AS
NO - 1753 Halden, Norway
Distributed by:
company logo
Whitehouse Station, NJ 08889, USA
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by
Schering Corporation.
Rx Only
02/11
©2011 Bayer HealthCare Pharmaceuticals Inc.
Printed In U.S.A.
Reference ID: 2910764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:46:10.646202
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11,790
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CIPRO®
(ciprofloxacin hydrochloride)
TABLETS
CIPRO®
(ciprofloxacin*)
ORAL SUSPENSION
81532304, R.1
02/09
WARNING:
Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis
and tendon rupture in all ages. This risk is further increased in older patients usually
over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants (See WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO
Tablets and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
DESCRIPTION
CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) Oral Suspension are
synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride,
USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light
yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is
C17H18FN3O3•HCl•H2Oand its chemical structure is as follows: Chemical Structure
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light
yellow crystalline substance and its chemical structure is as follows: Chemical Structure
CIPRO film-coated tablets are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent)
strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are cornstarch,
microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, hypromellose,
titanium dioxide, and polyethylene glycol.
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g
ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish
suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of
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ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See instructions for
USE/HANDLING). The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20.
Diluentmedium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
* Does not comply with USP with regard to “loss on drying” and “residue on ignition”.
CLINICAL PHARMACOLOGY
Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal
tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss
by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are
shown in the chart for the 250 mg to 1000 mg dose range.
Maximum
Area
Dose
Serum Concentration Under Curve (AUC)
(mg)
(µg/mL)
(µg•hr/mL)
250
1.2
4.8
500
2.4
11.6
750
4.3
20.2
1000
5.4
30.8
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12
hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimi
nation half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations
increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been
shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400
mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed
with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that
produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
Steady-state Pharmacokinetic Parameters
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7a
12.7a
31.6b
32.9c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
aAUC 0-12h
bAUC 24h=AUC0-12h x 2
cAUC 24h=AUC0-8h x 3
Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high
enough to cause significant protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations
often exceed serum concentrations in both men and women, particularly in genital tissue including the
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prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of
the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the
cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism: Four metabolites have been identified in human urine which together account for
approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less
active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450
1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs
primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs
and could lead to clinically significant adverse events of the coadministered drug (see
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4
hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 µg/mL during
the first two hours and are approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion
of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin,
which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120
mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the
ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately
20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from
either biliary clearance or transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing
250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO
Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10%
CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
Drug-drug Interactions: When CIPRO Tablet is given concomitantly with food, there is a delay in the
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather
than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The
overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The
pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Concurrent
administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the
bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS).
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline
resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other
adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See WARNINGS: PRECAUTIONS.)
Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and
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multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the
increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These
differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with
acute hepatic insufficiency, however, have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following
microorganisms, both in vitro and in clinical infections as described in the INDICATIONS
AND USAGE section of the package insert for CIPRO (ciprofloxacin hydrochloride) Tablets
and CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
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Streptococcus pyogenes
Aerobic gram-negative microorganisms
Campylobacter jejuni
Proteus mirabilis
Citrobacter diversus
Proteus vulgaris
Citrobacter freundii
Providencia rettgeri
Enterobacter cloacae
Providencia stuartii
Escherichia coli
Pseudomonas aeruginosa
Haemophilus influenzae
Salmonella typhi
Haemophilus parainfluenzae
Serratia marcescens
Klebsiella pneumoniae
Shigella boydii
Moraxella catarrhalis
Shigella dysenteriae
Morganella morganii
Shigella flexneri
Neisseria gonorrhoeae
Shigella sonnei
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin in treating clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains only)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Pasteurella multocida
Aeromonas hydrophila
Salmonella enteritidis
Edwardsiella tarda
Vibrio cholerae
Enterobacter aerogenes
Vibrio parahaemolyticus
Klebsiella oxytoca
Vibrio vulnificus
Legionella pneumophila
Yersinia enterocolitica
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are
resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and
Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
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For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible
aeruginosa a:
Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
MIC (µg/mL)
≤1
2
≥4
Interpretation
Susceptible
(S)
Intermediate (I)
Resistant
(R)
aThese interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
MIC (µg/mL)
Interpretation
≤1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
MIC (µg/mL)
Interpretation
≤ 0.06
Susceptible
(S)
0.12 – 0.5
Intermediate (I)
≥1
Resistant
(R)
c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined
growth supplement.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
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Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
C. jejunib
ATCC 33560
0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeaec
ATCC 49226
0.001-0.008
aThis quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
b C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller
Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37oC for
48 hours and for 42oC at 24 hours2, respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1%
defined growth supplement in a 5% CO2 environment at 35-37oC for 20-24 hours3.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 – 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using
Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
bThis zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)3.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
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For testing Neisseria gonorrhoeaec:
Zone Diameter (mm)
Interpretation
≥ 41
Susceptible
(S)
28 – 40
Intermediate (I)
≤ 27
Resistant
(R)
cThis zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined
growth supplement.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30 – 40
H. influenzaea
ATCC 49247
34 – 42
N. gonorrhoeaeb
ATCC 49226
48 – 58
P. aeruginosa
ATCC 27853
25 – 33
S. aureus
ATCC 25923
22 – 30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)3.
b These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226
performed by disk diffusion using GC agar base and 1% defined growth supplement.
INDICATIONS AND USAGE
CIPRO is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.
Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus
saprophyticus.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae,
Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus
pneumoniae, or Moraxella catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae,
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Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella
morganii,
Citrobacter
freundii,
Pseudomonas
aeruginosa,
methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
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Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni,
Shigella boydii †, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial
therapy is indicated.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been
demonstrated.
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.5
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
†Although treatment of infections due to this organism in this organ system demonstrated a clinically
significant outcome, efficacy was studied in fewer than 10 patients.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in
order to isolate and identify organisms causing infection and to determine their susceptibility to
ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once
results become available appropriate therapy should be continued. As with other drugs, some strains of
Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin.
Culture and susceptibility testing performed periodically during therapy will provide information not
only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial
resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets
and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral
Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be
caused by susceptible bacteria. When culture and susceptibility information are available, they should
be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO, are associated
with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most
frequently involves the Achilles tendon, and rupture of the Achilles tendon may require
surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the
biceps, the thumb, and other tendon sites have also been reported. The risk of developing
fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants. Factors, in addition to age and corticosteroid use, that may
independently increase the risk of tendon rupture include strenuous physical activity, renal
failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon
rupture have also occurred in patients taking fluoroquinolones who do not have the above risk
factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO should be discontinued
if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should
be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare
provider regarding changing to a non-quinolone antimicrobial drug.
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline,
methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and
could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure, and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin
may also cause central nervous system (CNS) events including: dizziness, confusion, tremors,
hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used
with caution in patients with known or suspected CNS disorders that may predispose to seizures or
lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other
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risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy,
renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions
and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus,
and respiratory failure. Although similar serious adverse effects have been reported in patients
receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin
cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be
monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone therapy.
Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be
administered as indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of
multiple doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or
any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CIPRO, and may range in
severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after
the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
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Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
Syphilis: Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial
agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms
of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time
of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after
three months.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL
PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans
because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving
ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions,
the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema,
exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V”
area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with
the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these
sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs
(See ADVERSE REACTIONS/Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
Prescribing CIPRO Tablets and CIPRO Oral Suspension in the absence of a proven or strongly
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Information for Patients:
Patients should be advised:
•to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or
weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
•that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used
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to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CIPRO
Tablets and CIPRO Oral Suspension is prescribed to treat a bacterial infection, patients should be
told that although it is common to feel better early in the course of therapy, the medication should be
taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by CIPRO Tablets and CIPRO Oral Suspension or
other antibacterial drugs in the future.
•that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other
quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or
sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered
drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may
be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken
with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of
ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that
contains these products.
•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones.
Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or
UVA/B treatment) while taking quinolones. If patients need to be outdoors while using
quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and
discuss other sun protection measures with their physician. If a sunburn-like reaction or skin
eruption occurs, patients should contact their physician.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know
how they react to this drug before they operate an automobile or machinery or engage in
activities requiring mental alertness or coordination.
•that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking quinolones.
•that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
• that diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can
develop watery and bloody stools (with or without stomach cramps and fever) even as late as
two or more months after having taken the last dose of the antibiotic. If this occurs, patients
should contact their physician as soon as possible.
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Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing
products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered
tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc
may substantially decrease its absorption, resulting in serum and urine levels considerably lower than
desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents
with ciprofloxacin.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of
ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions,
resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in
the level of ciprofloxacin in the serum. This should be considered if patients are receiving both
drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase
the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate
therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to
reach maximum plasma concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin, and the test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79Cell HGPRT Test (Negative)
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Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maxi
mum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32
weeks in mice treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance
of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and
well-controlled studies in pregnant women. An expert review of published data on experiences with
ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that
therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and
quality of data=fair), but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones
(52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero
exposure to fluoroquinolones during embryogenesis was not associated with increased risk of
major malformations. The reported rates of major congenital malformations were 2.2% for the
fluoroquinolone group and 2.6% for the control group (background incidence of major
malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not
differ between the groups and there were no clinically significant musculoskeletal dysfunctions up
to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
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exposed to ciprofloxacin during pregnancy.8,9 However, these small post-marketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate
the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during
pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see
WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and
100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based
upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended
therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.
For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including events related to joints and/or surrounding tissues. The
rates of these events in pediatric patients with complicated urinary tract infection and
pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6% (21/349) for
control agents. The rates of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless
of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
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and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age
were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders
including tendon rupture when being treated with a fluoroquinolone such as CIPRO. This risk
is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or
tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur
during or after completion of therapy; cases occurring up to several months after
fluoroquinolone treatment have been reported. Caution should be used when prescribing
CIPRO to elderly patients especially those on corticosteroids. Patients should be informed of
this potential side effect and advised to discontinue CIPRO and contact their healthcare
provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning,
WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals on any drug therapy cannot be ruled out.
Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse
reactions may be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function. However, since some
older individuals experience reduced renal function by virtue of their advanced age, care should be taken
in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT
interval. Therefore, precaution should be taken when using CIPRO with concomitant drugs that
can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in
patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected
hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1% of orally
treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),
diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients
are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in
extremities, injection site reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension,
angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis,
phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares,
hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy,
drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression,
paresthesia, abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation,
gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain,
flare up of gout
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary
retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
hemoptysis, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity/
phototoxicity reaction, flushing, fever, chills, angioedema, edema of the face, neck, lips,
conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum,
sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception,
overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad
taste, chromatopsia
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be
related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to
cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with
respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the
control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
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pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment.
An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of
overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin
cannot be excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, + 9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
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interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these events are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening
anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis,
fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure
(including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension
(postural), jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis
(oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity
reaction, potassium elevation (serum), prothrombin time prolongation or decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like
reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes,
toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also
INHALATIONAL ANTHRAXADDITIONAL INFORMATION.)
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without
regard to drug relationship are listed below:
Hepatic
– Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase
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(0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%),
elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal
– Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,
CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl
transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The
stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully
observed and given supportive treatment, including monitoring of renal function and administration of
magnesium, aluminum, or calcium containing antacids which can reduce the absorption of
ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%)
is removed from the body after hemodialysis or peritoneal dialysis.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats,
and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral
doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs
observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed
in these animals, occurring 10-14 days after dosing.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO Tablets and Oral Suspension should be administered orally to adults as described in the Dosage
Guidelines table.
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s
host-defense mechanisms, and the status of renal function and hepatic function.
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days;
however, for severe and complicated infections more prolonged therapy may be required.
Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum
antacids, or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral
solution, other highly buffered drugs, or other products containing calcium, iron or zinc.
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ADULT DOSAGE GUIDELINES
Infection
Severity
Dose
Frequency Usual Durations†
Urinary Tract
Acute Uncomplicated
250 mg
q 12 h
3 days
Mild/Moderate
250 mg
q 12 h
7 to 14 days
Severe/Complicated
500 mg
q 12 h
7 to 14 days
Chronic Bacterial
Mild/Moderate
500 mg
q 12 h
28 days
Prostatitis
Lower Respiratory Tract Mild/Moderate
500 mg
q 12 h
7 to 14 days
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Acute Sinusitis
Mild/Moderate
500 mg
q 12 h
10 days
Skin and
Mild/Moderate
500 mg
q 12 h
7 to 14 days
Skin Structure
Severe/Complicated
750 mg
q 12 h
7 to 14 days
Bone and Joint
Mild/Moderate
500 mg
q 12 h
≥ 4 to 6 weeks
Severe/Complicated
750 mg
q 12 h
≥ 4 to 6 weeks
Intra-Abdominal*
Complicated
500 mg
q 12 h
7 to 14 days
Infectious Diarrhea
Mild/Moderate/Severe
500 mg
q 12 h
5 to 7 days
Typhoid Fever
Mild/Moderate
500 mg
q 12 h
10 days
Urethral and Cervical
Uncomplicated
250 mg
single dose
single dose
Gonococcal Infections
Inhalational anthrax
500 mg
q 12 h
60 days
(post-exposure)**
* used in conjunction with metronidazole
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have
disappeared, except for inhalational anthrax (post-exposure).
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely
to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V.
may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the
physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens).
Equivalent AUC Dosing Regimens
Cipro Oral Dosage
Equivalent Cipro I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
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Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended, particularly for patients with severe renal dysfunction. The following table provides
dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dose
> 50
See Usual Dosage.
30 – 50
250 – 500 mg q 12 h
5 – 29
250 – 500 mg q 18 h
Patients on hemodialysis
250 – 500 mg q 24 h (after dialysis)
or Peritoneal dialysis
When only the serum creatinine concentration is known, the following formula may be used to estimate
creatinine clearance.
Men: Creatinine clearance (mL/min) =
Weight (kg) x (140 - age)
72 x serum creatinine (mg/dL)
Women: 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered
at the intervals noted above. Patients should be carefully monitored.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO Tablets and Oral Suspension should be administered orally as described in the Dosage
Guidelines table. An increased incidence of adverse events compared to controls, including
events related to joints and/or surrounding tissues, has been observed. (See ADVERSE
REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
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PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-
Exposure)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
HOW SUPPLIED
CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated
tablets containing 250 mg ciprofloxacin. The 250 mg tablet is coded with the word “BAYER” on one
side and “CIP 250” on the reverse side. CIPRO is also available as capsule shaped, slightly yellowish
film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet is coded with the
word “BAYER” on one side and “CIP 500” on the reverse side. The 750 mg tablet is coded with the
word “BAYER” on one side and “CIP 750” on the reverse side. CIPRO 250 mg, 500 mg, and 750 mg
are available in bottles of 50, 100, and Unit Dose packages of 100.
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Bottles of 50:
Strength
750 mg
NDC Code
NDC 0085-1756-01
Tablet Identification
CIPRO 750
Bottles of 100:
250 mg
NDC 0085-1758-01
CIPRO 250
500 mg
NDC 0085-1754-01
CIPRO 500
Unit Dose
Package of 100:
250 mg
NDC 0085-1758-02
CIPRO 250
500 mg
NDC 0085-1754-02
CIPRO 500
750 mg
NDC 0085-1756-02
CIPRO 750
Store below 30°C (86°F).
CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two
components (microcapsules containing the active ingredient and diluent) which must be mixed by the
pharmacist. See Instructions To The Pharmacist For Use/Handling.
Total volume
Ciprofloxacin
Ciprofloxacin
Strengths after reconstitution
Concentration
contents per bottle
NDC Code
5%
100 mL
250 mg/5 mL
5,000 mg
0085-1777-01
10%
100 mL
500 mg/5 mL
10,000 mg
0085-1773-01
Microcapsules and diluent should be stored below 25°C (77°F) and protected from freezing.
Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. A
teaspoon is provided for the patient.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in
juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal.
In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by
histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times
the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This
dose was also not associated with arthrotoxicity after an additional treatment-free period of 5
months. In another study, removal of weight bearing from the joint reduced the lesions but did not
totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced
hypotensive effects. These effects are considered to be related to histamine release, since they are
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also
produces hypotension but the effect in this species is inconsistent and less pronounced.
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In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone
and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days
Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by
Patient at 5 to 9 Days
Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new
infections.
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INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL
INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations. The mean peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional
information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in
humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL.6 Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day drug administration period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
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Usa
ge Illustration
Instructions To The Pharmacist For Use/Handling Of CIPRO Oral Suspension:
CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin
in 100 mL) strengths. The drug product is composed of two components (microcapsules and diluent)
which must be combined prior to dispensing.
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250 mg of ciprofloxacin.
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500 mg of ciprofloxacin.
Appropriate Dosing Volumes of the Oral Suspensions:
Dose
5%
10%
250 mg
5 mL
2.5 mL
500 mg
10 mL
5 mL
750 mg
15 mL
7.5 mL
Preparation of the suspension:
1. The small bottle
Usa
ge Illustration
2. Open both bottles.
contains the
Child-proof cap: Press
microcapsules, the
down according to
large bottle
instructions on the cap
contains the
while turning to the
diluent.
left.
3. Pour the
4. Remove the top layer
microcapsules
of the diluent bottle
completely into the
label (to reveal the
larger bottle of
CIPRO Oral
diluent. Do not add
Suspension label).
water to the
Close the large bottle
suspension.
completely according
to the directions on the
cap and shake
vigorously for about
15 seconds. The
suspension is ready for
use.
CIPRO Oral Suspension should not be administered through feeding tubes due to its
physical characteristics.
Instruct the patient to shake CIPRO Oral Suspension vigorously each time before use for
approximately 15 seconds and not to chew the microcapsules.
Bayer Response 12 Feb 2009
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References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline.,
CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
3. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard NCCLS
Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s
Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA,
CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening
Illnesses). 6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J
Infect Dis 1993; 167:1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS).
Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6):1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone
exposure. Evaluation of a case registry of the European network of teratology information services
(ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
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MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place
of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO can cause side effects
that may be serious or even cause death. If you get any of the following serious side effects, get
medical help right away. Talk with your healthcare provider about whether you should
continue to take CIPRO.
• Tendon rupture or swelling of the tendon (tendinitis)
• Tendons are tough cords of tissue that connect muscles to bones.
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take
fluoroquinolone antibiotics, including CIPRO. The risk of getting tendon problems is
higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in
patients who take fluoroquinolones who do not have the above risk factors.
• Other reasons for tendon ruptures can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or
inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by
your healthcare provider. Avoid exercise and using the affected area. The most common
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area of pain and swelling is the Achilles tendon at the back of your ankle. This can also
happen with other tendons. Talk to your healthcare provider about the risk of tendon
rupture with continued use of CIPRO. You may need a different antibiotic that is not a
fluoroquinolone to treat your infection.
• Tendon rupture can happen while you are taking or after you have finished taking CIPRO.
Tendon ruptures have happened up to several months after patients have finished taking their
fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a tendon
rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
• See the section “What are the possible side effects of CIPRO?” for more information
about side effects.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain
germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon
(musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be
used as the first choice of antibiotic medicine in children under 18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children under
18 years old, except to treat specific serious infections, such as complicated urinary tract
infections and to prevent anthrax disease after breathing the anthrax bacteria germ (inhalational
exposure). It is not known if CIPRO XR is safe and works in children under 18 years of age.
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral
infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including
CIPRO, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are
taking CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
• have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are
allergic to any of the ingredients in CIPRO. Ask your healthcare provider if you are not sure.
See the list of ingredients in CIPRO at the end of this Medication Guide.
• also take a medicine called tizanidine (Zanaflex®). Serious side effects from tizanidine are
likely to happen.
What should I tell my healthcare provider before taking CIPRO?
See “What is the most important information I should know about CIPRO?”
Tell your healthcare provider about all your medical conditions, including if
you:
• have tendon problems
• have central nervous system problems (such as epilepsy)
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• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work
well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your
unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other
medicines can affect each other causing side effects. Especially tell your healthcare provider if
you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain
relief are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones
may increase your risk of central nervous system effects and seizures. See "What are the
possible side effects of CIPRO?".
• a blood thinner (warfarin, Coumadin®, Jantoven®)
• tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine. See
“Who should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible side
effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended Phenytoin
Sodium®, Prompt Penytoin Sodium®, Phenytek®)
• products that contain caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the
possible side effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance
of tendon injury. See “What is the most important information I should know about
CIPRO?”
• methotrexate (Trexall®)
• Probenecid (Probalan®, Col-probenecid®)
• Metoclopromide (Reglan®, Reglan ODT®)
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from working
correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after
taking these products:
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• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum,
iron, or zinc
• sucralfate (Carafate®)
• didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you
can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day.
Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to
make sure the suspension is mixed well. Close the bottle completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet
whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified
juices alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you
finish your prescribed treatment, unless:
• you have tendon effects (see “What is the most important information I should
know about CIPRO?”),
• you have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
• your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic
medicines may not work in the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember.
Do not take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than
one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
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If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO
I.V. after being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance of getting
anthrax disease or worsening of the disease after you are exposed to the anthrax bacteria
germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking CIPRO
without talking with your healthcare provider. If you stop taking CIPRO too soon, it may
not keep you from getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or I.V.
When taking your CIPRO to prevent anthrax infection, you and your healthcare provider
should talk about whether the risks of stopping CIPRO too soon are more important than
the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets, Oral
Suspension or I.V. for anthrax are more important than the risks.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do
other activities that require mental alertness or coordination until you know how CIPRO
affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make your
skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds.
You could get severe sunburn, blisters or swelling of your skin. If you get any of these
symptoms while taking CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the
most important information I should know about CIPRO?”
Other serious side effects of CIPRO include:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics including
CIPRO. Tell your healthcare provider if you have a history of seizures. Ask your healthcare
provider whether taking CIPRO will change your risk of having a seizure.
Central Nervous System (CNS) side effects may happen as soon as after taking the first
dose of CIPRO. Talk to your healthcare provider right away if you get any of these side
effects, or other changes in mood or behavior:
• feel dizzy
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
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• trouble sleeping
• nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even
after only one dose. Stop taking CIPRO and get emergency medical help right away if you
get any of the following symptoms of a severe allergic reaction:
• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right
away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a
sign of a more serious reaction to CIPRO.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or
irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as
prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be
very dangerous. The chances of this event are higher in people:
• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or
bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can
happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Talk with your healthcare provider right away if you
get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or
feet:
• pain
• burning
• tingling
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• numbness
• weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes
medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar
(hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low
blood sugar with CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18
years old. Tell your child’s healthcare provider if your child has any joint problems during
or after treatment with CIPRO.
The most common side effects of CIPRO include:
• nausea
• headache
• diarrhea
• vomiting
• vaginal yeast infection
• changes in liver function tests
• pain or discomfort in the abdomen
These are not all the possible side effects of CIPRO. Tell your healthcare provider about any side
effect that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely
thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If you would
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like more information about CIPRO, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about CIPRO that is written for healthcare
professionals. For more information go to www.CIPRO.com or call 1-800-526-4099.
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene
glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following compositions:
Microcapsulesciprofloxacin, povidone, methacrylic acid copolymer, hypromellose,
magnesium stearate, and Polysorbate 20. Diluentmedium-chain triglycerides, sucrose,
lecithin, water, and strawberry flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
Revised October 2008
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Company logo
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
Company logo
Schering Corporation
Kenilworth, NJ 07033
CIPRO is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering
Bayer Response 12 Feb 2009
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Corporation.
Rx Only
81532304, R.1
02/09
Bay o 9867
5202-2-A-U.S.-26
©2009 Bayer HealthCare Pharmaceuticals Inc.
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
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CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
81532266, R.1
02/09
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis
and tendon rupture in all ages. This risk is further increased in older patients usually over 60
years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or
lung transplants (See WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3and its chemical structure is: Chemcial Structure
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for
the 1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP
biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
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Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q12h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg
administered intravenously. Comparison of the pharmacokinetic parameters following the 1st
and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no
substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin
given over 60 minutes every 12 hours has been shown to produce an area under the serum
concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every
12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8
hours has been shown to produce an AUC at steady-state equivalent to that produced by a
750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that
observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours
produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
AUC (µg•hr/mL)
Cmax (µg/mL)
500 mg
q12h, P.O.
13.7 a
2.97
400 mg
q12h, I.V.
12.7 a
4.56
750 mg
q12h, P.O.
31.6 b
3.59
400 mg
q8h, I.V.
32.9 c
4.07
a AUC0-12h
bAUC 24h=AUC0-12h × 2
cAUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial
secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It
has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug
diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak
serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are
lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human
urine which together account for approximately 10% of the intravenous dose. The binding of
ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin
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with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations
of these drugs and could lead to clinically significant adverse events of the coadministered drug
(see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35
L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in
the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually
exceed 200 µg/mL 0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours
after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL
0–2 hours after dosing and are usually greater than 30 µg/mL 8–12 hours after dosing. The
renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually
complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum
concentrations after intravenous dosing, only a small amount of the administered dose (< 1%)
is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered
from the feces within 5 days after dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean
AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the
elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in
patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in
age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the
mean AUC was 9.2 µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent
age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour
infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 – 8.3 µg/mL) in 10 children less than 1 year
of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10 children between 1 and 5 years of age.
The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0 µg*h/mL) and 16.5 µg*h/mL (range:
11.0 – 23.8 µg*h/mL) in the respective age groups. These values are within the range reported
for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 - 5
hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
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PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly
by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of
serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
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Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant
to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate
(I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests
with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or in situations where high
dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled
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technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide
the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
C. jejunib
ATCC 33560
0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeaec
ATCC 49226
0.001-0.008
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
b C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller
Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37oC for
48 hours and for 42oC at 24 hours2, respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1%
defined growth supplement in a 5% CO2 environment at 35-37oC for 20-24 hours3.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with
a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus
species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
aThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)3.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
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a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)3.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the
designated microorganisms in the conditions and patient populations listed below when the
intravenous administration offers a route of administration advantageous to the patient. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus
pneumoniae, or Moraxella catarrhalis.
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Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues. (See WARNINGS,
PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.)
Ciprofloxacin,
like
other
fluoroquinolones,
is
associated
with
arthropathy
and
histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL
PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.5
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was
obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy
with CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are
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associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse
reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may
require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand,
the biceps, the thumb, and other tendon sites have also been reported. The risk of developing
fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients
usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants. Factors, in addition to age and corticosteroid use, that may
independently increase the risk of tendon rupture include strenuous physical activity, renal
failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon
rupture have also occurred in patients taking fluoroquinolones who do not have the above risk
factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be
discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon.
Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact
their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only
for infections listed in the INDICATIONS AND USAGE section. An increased incidence of
adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent
lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline,
methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and
could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic
psychosis have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all
quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS
disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or
lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS:
General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
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CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure,
status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in
patients receiving theophylline alone, the possibility that these reactions may be potentiated by
ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to
uncertain etiology, have been reported rarely in patients receiving therapy with quinolones,
including ciprofloxacin. These events may be severe and generally occur following the
administration of multiple doses. Clinical manifestations may include one or more of the
following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or
any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CIPRO, and may range in
severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after
the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy
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including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in
light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in
order to prevent the development of an irreversible condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with
the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
(See WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions,
the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema,
exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V”
area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with
the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these
sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs
(See ADVERSE REACTIONS/ Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
•to contact their healthcare provider if they experience pain, swelling, or inflammation of a
tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and
discontinue CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones
is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs,
and in patients with kidney, heart or lung transplants.
•that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to
treat a bacterial infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or
not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by CIPRO I.V. or other antibacterial drugs in the future.
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•that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
•that photosensitivity/phototoxicity has been reported in patients receiving quinolones.
Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or
UVA/B treatment) while taking quinolones. If patients need to be outdoors while using
quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and
discuss other sun protection measures with their physician. If a sunburn-like reaction or skin
eruption occurs, patients should contact their physician.
•that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
•that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
•that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop,
they should discontinue treatment and contact their physicians.
•that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
•that ciprofloxacin has been associated with an increased rate of adverse events involving
joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years
of age). Parents should inform their child’s physician if the child has a history of joint-related
problems before taking this drug. Parents of pediatric patients should also notify their child’s
physician of any joint-related problems that occur during or following ciprofloxacin therapy.
(See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
•that diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can
develop watery and bloody stools (with or without stomach cramps and fever) even as late as
two or more months after having taken the last dose of the antibiotic. If this occurs, patients
should contact their physician as soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments
made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
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The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral
anticoagulant warfarin or its derivatives. When these products are administered concomitantly,
prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems
gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice,
respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose
based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
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treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg
(approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2)
revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but
the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.8,9 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for
less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in
pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless
the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6
and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose
levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic
dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an
increased incidence of abortion, but no teratogenicity was observed at either dose level. After
intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest
recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no
embryotoxicity or teratogenicity was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological
changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
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PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is
appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure),
see DOSAGE
AND
ADMINISTRATION and INHALATIONAL
ANTHRAX
–
ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and
pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the pediatric population due to an increased incidence of adverse events
compared to the controls, including those related to joints and/or surrounding tissues. The rates
of these events in pediatric patients with complicated urinary tract infection and pyelonephritis
within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents.
The rates of these events occurring at any time up to the one year follow-up were 13.7%
(46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug
relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31%
(109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in
cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose
q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21
days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h
and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of
age were not studied. Safety monitoring in the study included periodic range of motion
examinations and gait assessments by treatment-blinded examiners. Patients were followed for
an average of 23 days after completing treatment (range 0-93 days). This study was not
designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the
patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of
motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the
comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group
and 11% in the comparison group. Other adverse events were similar in nature and frequency
between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days
after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI
showed knee effusion without other abnormalities eight months after treatment. However, the
relationship of this event to the patient’s course of ciprofloxacin can not be definitively
determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as
part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders
including tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This
risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or
tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur
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during or after completion of therapy; cases occurring up to several months after
fluoroquinolone treatment have been reported. Caution should be used when prescribing
CIPRO I.V. to elderly patients especially those on corticosteroids. Patients should be informed
of this potential side effect and advised to discontinue CIPRO I.V. and contact their healthcare
provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning,
WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin
encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or
equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall
differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy
cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the
risk of adverse reactions may be greater in patients with impaired renal function. No alteration
of dosage is necessary for patients greater than 65 years of age with normal renal function.
However, since some older individuals experience reduced renal function by virtue of their
advanced age, care should be taken in dose selection for elderly patients, and renal function
monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported
were described as only mild or moderate in severity, abated soon after the drug was
discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all
dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous
system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia,
headache, restlessness, and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V.
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as
local skin reactions which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of
administration, that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
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CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial
infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
hypertension,
hypotension,
angina
pectoris,
atrial
flutter,
ventricular
ectopy,
(thrombo)-phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated
diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation,
dyspepsia, epigastric pain, constipation, oral ulceration, oral candidiasis, mouth dryness,
anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention,
gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and
albuminuria have also been reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary
edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
allergic
reactions,
anaphylactic
reactions
including
life-threatening anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative
dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae,
hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis,
vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning,
paresthesia, erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and
Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal
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and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335
ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal
adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included
such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back
pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of
treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated
group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were
mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved
(clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The
events occurred more frequently in ciprofloxacin-treated patients than control patients,
regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were
more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events
reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group
versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed
that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence
interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the
control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included
dizziness, nervousness, insomnia, and somnolence.
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In this trial, the overall incidence rates of adverse events regardless of relationship to study
drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group
versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients.
Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared
to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was
observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were
diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%,
dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected
that events reported in adults during clinical trials or post-marketing experience may also occur
in pediatric patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with quinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure. Decisions to include
these events in labeling are typically based on one or more of the following factors: (1) seriousness
of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum),
confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative
dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic
failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia,
hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia,
moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible
exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity
reaction, potassium elevation (serum), prothrombin time prolongation or decrease,
pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like
reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes,
toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching,
vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax
post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also
INHALATIONAL ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
— elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and
serum bilirubin
Hematologic — elevated eosinophil and platelet counts, decreased platelet
counts, hemoglobin and/or hematocrit
Renal
— elevations of serum creatinine, BUN, and uric acid
Other
— elevations of serum creatine phosphokinase, serum theophylline
(in patients receiving theophylline concomitantly), blood glucose, and triglycerides
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Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60
minutes at dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a
larger vein will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation
of CIPRO I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Bayer Response I.V. 12 Feb 2009.doc
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Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax (post-exposure) is
60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for
oral administration are available. Parenteral therapy may be switched to oral CIPRO when the
condition warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table
below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the
liver and through the intestine. These alternative pathways of drug elimination appear to
compensate for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended for patients with severe renal dysfunction. The
following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
Bayer Response I.V. 12 Feb 2009.doc
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72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased
incidence of adverse events compared to controls, including events related to joints and/or surrounding
tissues, has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial
was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus
anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical
trial of complicated urinary tract infection and pyelonephritis. No information is available on
Bayer Response I.V. 12 Feb 2009.doc
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dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency
(i.e., creatinine clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of
CIPRO I.V. This should be diluted with a suitable intravenous solution to a final concentration of
1–2mg/mL. (See COMPATIBILITY AND STABILITY.) The resulting solution should be infused
over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may
already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue
temporarily the administration of any other solutions during the infusion of CIPRO I.V. If the
concomitant use of CIPRO I.V. and another drug is necessary each drug should be given separately in
accordance with the recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Hospira,
Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Baxter
Healthcare Corporation, Deerfield, IL 60015.
Bayer Response I.V. 12 Feb 2009.doc
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SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mL 5% Dextrose
200 mg, 0.2%
400 mg, 0.2%
0085-1781-01
0085-1762-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant
improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded
in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving
Bayer Response I.V. 12 Feb 2009.doc
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500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every
12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2
µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL,
following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the
second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean
peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects
on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For
additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations
achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and
provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In
the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean
steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL.6
Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin
beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group
(9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the
30-day drug administration period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin
was recommended to most of those individuals for all or part of the prophylaxis regimen. Some
persons were also given anthrax vaccine or were switched to alternative antibiotics. No one
who received ciprofloxacin or other therapies as prophylactic treatment subsequently
developed inhalational anthrax. The number of persons who received ciprofloxacin as all or
part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000
reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax.
Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological
adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and
musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more
frequent than had been previously reported in controlled clinical trials. This higher incidence,
in the absence of a control group, could be explained by a reporting bias, concurrent medical
conditions, other concomitant medications, emotional stress or other confounding factors,
and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in
the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin
sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Bayer Response I.V. 12 Feb 2009.doc
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Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented);
(3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric
Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the
pediatric population due to an increased incidence of adverse events compared to controls,
including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment
of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17
years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina,
Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21
days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary
objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline
organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or
TOC). The Per Protocol population had a causative organism(s) with protocol specified colony
count(s) at baseline, no protocol violation, and no premature discontinuation or loss to
follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were
similar between ciprofloxacin and the comparator group as shown below.
Bayer Response I.V. 12 Feb 2009.doc
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Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total
number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator
patients with superinfections or new infections.
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard
NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline.,
CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
3. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS
Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products
Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA,
CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200,
Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening
Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during
prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J
Infect Dis 1993; 167: 1239-42.
Bayer Response I.V. 12 Feb 2009.doc
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS).
Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone
exposure. Evaluation of a case registry of the European network of teratology information
services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:10.932012
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s69,19847s43,19857s50,20780s27lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 50}
|
11,792
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7/11
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is: structural formula
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Reference ID: 3000237
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
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MICROBIOLOGY
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair,
and recombination.
Drug Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin and other fluoroquinolones. There
is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro
resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due
to spontaneous mutations occurs in vitro at a general frequency of between < 10-9 to 1x10-6.
Activity in vitro and in vivo
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not
exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
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The following in vitro data are available, but their clinical significance is unknown. Ciprofloxacin
exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥ 90%)
strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin
intravenous formulations in treating clinical infections due to these microorganisms have not been
established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
• Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of
bacteria to antimicrobial compounds. The MICs should be determined using a standardized
procedure. Standardized procedures are based on a dilution method1 (broth or agar) or
equivalent with standardized inoculum concentrations and standardized concentrations of
ciprofloxacin powder. The MIC values should be interpreted according to the criteria
outlined in Table 1.
• Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of
microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a
5-µg ciprofloxacin disk should be interpreted according to the criteria outlined in Table 1.
Interpretation involves correlation of the diameter obtained in the disk test with the MIC for
ciprofloxacin.
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Table 1: Susceptibility Interpretive Criteria for Ciprofloxacin
MIC (μg/mL)
Zone Diameter (mm)
Species
S
I
R
S
I
R
Enterobacteriacae
≤1
2
≥4
≥21
16-20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16-20
≤15
Methicillin susceptible
Staphylococcus species
≤1
2
≥4
≥21
16-20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16-20
≤15
Haemophilus influenzae
≤1a
e
e
≥21b
e
e
Haemophilus parainfluenzae
≤1a
e
e
≥21b
e
e
Penicillin susceptible
Streptococcus pneumoniae
≤1c
2c
≥4c
≥21d
16-20d
≤15d
Streptococcus pyogenes
≤1c
2c
≥4c
≥21d
16-20d
≤15d
S=susceptible, I=Intermediate, and R=resistant.
a This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)1 .
b This zone diameter standard is applicable only to tests with Haemophilus influenzae using Haemophilus Test
Medium (HTM)3 .
c These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
dThese zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar
supplemented with 5% sheep blood incubated in 5% CO2.
eThe current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding
zone diameter results suggestive of a “Non-Susceptible” category should be submitted to a reference laboratory for
further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
• Quality Control: Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures. For dilution
technique, standard ciprofloxacin powder should provide the following MIC values: standard
ciprofloxacin powder should give the MIC values provided in Table 2. For diffusion technique, the
5-µg ciprofloxacin disk should provide the zone diameters outlined in Table 2.
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Table 2: Quality Control for Susceptibility Testing
Strains
MIC range (μg/mL)
Zone Diameter
(mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03a
34–42b
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC29213
0.12–0.5
-
Staphylococcus aureus ATCC25923
-
22–30
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1 .
b These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus
Test Medium (HTM)3 .
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
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aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
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Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If
these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and
appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in
patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction).
(See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
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fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
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Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
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Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
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malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.8,9 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
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fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
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SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with flouroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
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decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
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Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
7-14 Days
7-14 Days
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
≥ 4-6 Weeks
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
28 Days
Empirical Therapy
in
Severe
Febrile Neutropenic
Patients
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
Not to exceed
q8h
q4h
7-14 Days
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
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750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
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(patients from
1 to 17 years of
age)
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
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5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V.
is available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
STRENGTH
NDC NUMBER
20 mL
200 mg, 1%
0085-1763-03
40 mL
400 mg, 1%
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Hospira, Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Baxter Healthcare Corporation, Deerfield, IL 60015.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1781-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1762-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1759-01
200 mL 5% Dextrose
400 mg, 0.2%
0085-1782-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF).
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
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* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
NDA 019857 Cipro IV Microbiology Update 06 July 2011
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PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL6. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
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Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
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95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests
for Bacteria That Grow Aerobically; Approved Standard – Eighth Edition. CLSI Document M7-A8,
Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009.
2. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second
Edition. CLSI Document M45-A2, CLSI, Wayne, PA, January, 2010.
3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk
Susceptibility Tests; Approved Standard – Tenth Edition. CLSI Document M2-A10, Vol. 29, No. 1,
CLSI, Wayne, PA, January, 2009.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
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MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
READ THE MEDICATION GUIDE THAT COMES WITH CIPRO® BEFORE YOU START TAKING IT AND EACH
TIME YOU GET A REFILL. THERE MAY BE NEW INFORMATION. THIS MEDICATION GUIDE DOES NOT TAKE
THE PLACE OF TALKING TO YOUR HEALTHCARE PROVIDER ABOUT YOUR MEDICAL CONDITION OR YOUR
TREATMENT.
What is the most important information I should know about CIPRO?
CIPRO BELONGS TO A CLASS OF ANTIBIOTICS CALLED FLUOROQUINOLONES. CIPRO CAN CAUSE SIDE
EFFECTS THAT MAY BE SERIOUS OR EVEN CAUSE DEATH. IF YOU GET ANY OF THE FOLLOWING
SERIOUS SIDE EFFECTS, GET MEDICAL HELP RIGHT AWAY. TALK WITH YOUR HEALTHCARE PROVIDER
ABOUT WHETHER YOU SHOULD CONTINUE TO TAKE CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis)
• Tendon problems can happen in people of all ages who take CIPRO. Tendons are
tough cords of tissue that connect muscles to bones. Symptoms of tendon problems
may include:
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
•
The risk of getting tendon problems while you take CIPRO is higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO. Other reasons that can increase your risk of
tendon problems can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or
inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by
your healthcare provider. Avoid exercise and using the affected area. The most common
area of pain and swelling is the Achilles tendon at the back of your ankle. This can also
happen with other tendons.
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• Talk to your healthcare provider about the risk of tendon rupture with continued use
of CIPRO. You may need a different antibiotic that is not a fluoroquinolone to treat your
infection.
• Tendon rupture can happen while you are taking or after you have finished taking
CIPRO. Tendon ruptures have happened up to several months after patients have
finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a
tendon rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
2. WORSENING OF MYASTHENIA GRAVIS (A DISEASE WHICH CAUSES MUSCLE WEAKNESS).
FLUOROQUINOLONES LIKE CIPRO MAY CAUSE WORSENING OF MYASTHENIA GRAVIS SYMPTOMS,
INCLUDING MUSCLE WEAKNESS AND BREATHING PROBLEMS. CALL YOUR HEALTHCARE PROVIDER
RIGHT AWAY IF YOU HAVE ANY WORSENING MUSCLE WEAKNESS OR BREATHING PROBLEMS.
SEE THE SECTION “WHAT ARE THE POSSIBLE SIDE EFFECTS OF CIPRO?” FOR MORE INFORMATION
ABOUT SIDE EFFECTS.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused
by certain germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or
tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO.
CIPRO should not be used as the first choice of antibiotic medicine in children under 18
years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children
under 18 years old, except to treat specific serious infections, such as complicated
urinary tract infections and to prevent anthrax disease after breathing the anthrax
bacteria germ (inhalational exposure). It is not known if CIPRO XR is safe and works in
children under 18 years of age.
SOMETIMES INFECTIONS ARE CAUSED BY VIRUSES RATHER THAN BY BACTERIA. EXAMPLES INCLUDE
VIRAL INFECTIONS IN THE SINUSES AND LUNGS, SUCH AS THE COMMON COLD OR FLU. ANTIBIOTICS,
INCLUDING CIPRO, DO NOT KILL VIRUSES.
CALL YOUR HEALTHCARE PROVIDER IF YOU THINK YOUR CONDITION IS NOT GETTING BETTER WHILE
YOU ARE TAKING CIPRO.
Who should not take CIPRO?
DO NOT TAKE CIPRO IF YOU:
•
HAVE EVER HAD A SEVERE ALLERGIC REACTION TO AN ANTIBIOTIC KNOWN AS A
FLUOROQUINOLONE, OR ARE ALLERGIC TO ANY OF THE INGREDIENTS IN CIPRO. ASK YOUR
HEALTHCARE PROVIDER IF YOU ARE NOT SURE. SEE THE LIST OF INGREDIENTS IN CIPRO AT THE
END OF THIS MEDICATION GUIDE.
•
ALSO TAKE A MEDICINE CALLED TIZANIDINE (ZANAFLEX®). SERIOUS SIDE EFFECTS FROM
TIZANIDINE ARE LIKELY TO HAPPEN.
What should I tell my healthcare provider before taking CIPRO?
SEE “WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT CIPRO?”
Tell your healthcare provider about all your medical conditions, including if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis) have central nervous
system problems (such as epilepsy)
Reference ID: 3000237
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• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work
well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your
unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other
medicines can affect each other causing side effects. Especially tell your healthcare provider if
you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief
are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may
increase your risk of central nervous system effects and seizures. See "What are the
possible side effects of CIPRO?"
• a blood thinner (warfarin, Coumadin®, Jantoven®)
•
tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine.
See “Who should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
•
glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible
side effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium
®, Dilantin-125®, Dilantin®, Extended
Phenytoin Sodium
, Cerebyx
®
®, Phenytek )
• products that contain
, Prompt Penyto
®
in Sodium
caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the
possible side effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance
of tendon injury. See “What is the most important information I should know about
CIPRO?”
•
methotrexate (Trexall®
•
Probenecid (Probalan®, Col-probenecid®
•
Metoclopromide (Reglan®
)
• Certain medicines may keep
,
)
Reglan ODT
CIPRO Tablet
)
s
®
, CIPRO Oral Suspension from working
correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after
taking these products:
• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron,
or zinc
•
sucralfate (Carafate®)
•
didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are
listed above.
KNOW THE MEDICINES YOU TAKE. KEEP A LIST OF YOUR MEDICINES AND SHOW IT TO YOUR
HEALTHCARE PROVIDER AND PHARMACIST WHEN YOU GET A NEW MEDICINE.
Reference ID: 3000237
®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you
can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day.
Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to
make sure the suspension is mixed well. Close the bottle completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet
whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you finish
your prescribed treatment, unless:
•
you have tendon effects (see “What is the most important information I should
know about CIPRO?”),
•
you have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
•
your healthcare provider tells you to stop.
This will help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic
medicines may not work in the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember.
Do not take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than
one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V.
after being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance
of getting anthrax disease or worsening of the disease after you are exposed to the
anthrax bacteria germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking
CIPRO without talking with your healthcare provider. If you stop taking CIPRO too
soon, it may not keep you from getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or
I.V. When taking your CIPRO to prevent anthrax infection, you and your healthcare
provider should talk about whether the risks of stopping CIPRO too soon are more
important than the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets, Oral
Suspension or I.V. for anthrax are more important than the risks.
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do
other activities that require mental alertness or coordination until you know how CIPRO
affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make
your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning
beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these
symptoms while taking CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the
most important information I should know about CIPRO?”
OTHER SERIOUS SIDE EFFECTS OF CIPRO INCLUDE:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics
including CIPRO. Tell your healthcare provider if you have a history of seizures. Ask
your healthcare provider whether taking CIPRO will change your risk of having a
seizure.
CENTRAL NERVOUS SYSTEM (CNS) SIDE EFFECTS MAY HAPPEN AS SOON AS AFTER TAKING THE
FIRST DOSE OF CIPRO. TALK TO YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU GET ANY OF
THESE SIDE EFFECTS, OR OTHER CHANGES IN MOOD OR BEHAVIOR:
• feel dizzy
•
seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
•
tremors
• feel anxious or nervous
•
confusion
•
depression
• trouble sleeping
•
nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even
after only one dose. Stop taking CIPRO and get emergency medical help right away if you
get any of the following symptoms of a severe allergic reaction:
•
hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
•
faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right
away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a
sign of a more serious reaction to CIPRO.
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or
irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as
prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be
very dangerous. The chances of this event are higher in people:
• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or
bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can
happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Talk with your healthcare provider right away if you get
any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
•
pain
•
burning
•
tingling
•
numbness
•
weakness
CIPRO MAY NEED TO BE STOPPED TO PREVENT PERMANENT NERVE DAMAGE.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes
medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar
(hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get
low blood sugar with CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18
years old. Tell your child’s healthcare provider if your child has any joint problems during or
after treatment with CIPRO.
THE MOST COMMON SIDE EFFECTS OF CIPRO INCLUDE:
•
nausea
•
headache
•
diarrhea
•
vomiting
• vaginal yeast infection
• changes in liver function tests
•
pain or discomfort in the abdomen
THESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF CIPRO. TELL YOUR HEALTHCARE PROVIDER
ABOUT ANY SIDE EFFECT THAT BOTHERS YOU, OR THAT DOES NOT GO AWAY.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO
FDA AT 1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely
thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
KEEP CIPRO AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.
General Information about CIPRO
MEDICINES ARE SOMETIMES PRESCRIBED FOR PURPOSES OTHER THAN THOSE LISTED IN A
MEDICATION GUIDE. DO NOT USE CIPRO FOR A CONDITION FOR WHICH IT IS NOT PRESCRIBED. DO
NOT GIVE CIPRO TO OTHER PEOPLE, EVEN IF THEY HAVE THE SAME SYMPTOMS THAT YOU HAVE. IT
MAY HARM THEM.
THIS MEDICATION GUIDE SUMMARIZES THE MOST IMPORTANT INFORMATION ABOUT CIPRO. IF YOU
WOULD LIKE MORE INFORMATION ABOUT CIPRO, TALK WITH YOUR HEALTHCARE PROVIDER. YOU CAN
ASK YOUR HEALTHCARE PROVIDER OR PHARMACIST FOR INFORMATION ABOUT CIPRO THAT IS
WRITTEN FOR HEALTHCARE PROFESSIONALS. FOR MORE INFORMATION CALL 1-888-84 BAYER (1-888
842-2937).
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone,
magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following
compositions:
Microcapsulesciprofloxacin,
povidone,
methacrylic
acid
copolymer,
hypromellose,
magnesium
stearate,
and
Polysorbate
20.
Diluentmedium-chain triglycerides, sucrose, lecithin, water, and strawberry
flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH
adjustment
Revised June 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
06/11
©2011 Bayer HealthCare Pharmaceuticals Inc.
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
Reference ID: 3000237
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:10.953841
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019847s050,019857s057lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 57}
|
11,793
|
structural formula
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
07/11
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
Reference ID: 3030756
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After 60-minute I.V. Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, I.V.
q12h, P.O.
q8h, I.V.
AUC (µg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (µg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
2
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
MICROBIOLOGY
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA
replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides,
macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be
susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between
3
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by
multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when
tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal
inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against
most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of
ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have
not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Reference ID: 3030756
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosaa :
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
2
Intermediate (I)
≥ 4
Resistant
(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (µg/mL)
Interpretation
≤ 1
Susceptible
(S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with
Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
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report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should
provide the following MIC values:
Organism
MIC (µg/mL)
E. faecalis
ATCC 29212
0.25 – 2.0
E. coli
ATCC 25922
0.004 – 0.015
H. influenzaea
ATCC 49247
0.004 – 0.03
P. aeruginosa
ATCC 27853
0.25 – 1.0
S. aureus
ATCC 29213
0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg
ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species,
penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas
aeruginosa a :
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
16 - 20
Intermediate (I)
≤ 15
Resistant
(R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-
Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)
Interpretation
≥ 21
Susceptible
(S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium (HTM)2.
The current absence of data on resistant strains precludes defining any results other than “Susceptible”.
Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to
a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these
laboratory test quality control strains:
Organism
Zone Diameter (mm)
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E. coli
ATCC 25922
30-40
H. influenzae a
ATCC 49247
34-42
P. aeruginosa
ATCC 27853
25-33
S. aureus
ATCC 25923
22-30
a These quality control limits are applicable to only H. influenzae ATCC 49247 testing using
Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also,
Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of
presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible
Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
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related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
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and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
Central Nervous System Disorders: Convulsions, increased intracranial pressure (including
pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones,
including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including:
dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin,
the drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones,
ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may
predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or
in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g.
certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients,
Drug Interaction and ADVERSE REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
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Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small
and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
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PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
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• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead
to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
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Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
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exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.7
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluo
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).9 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
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involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
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hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
Reference ID: 3030756
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An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
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Reference ID: 3030756
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seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic
elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other
elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
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OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
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(post-exposure)**
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
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DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administratio
n
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
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Reference ID: 3030756
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Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available in a clear, colorless to slightly yellowish solution. CIPRO I.V. is
available in a 400 mg strength. The premixed solution is supplied in latex-free flexible containers as
follows:
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
STRENGTH
NDC NUMBER
200 mL 5% Dextrose
400 mg, 0.2%
50419-759-01
STORAGE
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
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Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
24
Reference ID: 3030756
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PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.6
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Reference ID: 3030756
25
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Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
26
Reference ID: 3030756
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
References:
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial
Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20,
No. 1, NCCLS, Wayne, PA, January, 2000.
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
6. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
8. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
Reference ID: 3030756
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:10.987233
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1
CIPRO® IV
(ciprofloxacin)
For Intravenous Infusion
07/13
WARNING:
Fluoroquinolones, including CIPRO® IV, are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO IV, may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and
other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO IV (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (IV)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
structural formula
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in
dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions are available
as sterile 1% aqueous concentrates, which are intended for dilution prior to administration, and as 0.2%
ready-for-use infusion solutions in 5% Dextrose Injection. All formulas contain lactic acid as a solubilizing agent
and hydrochloric acid for pH adjustment. The pH range for the 1% aqueous concentrates in vials is 3.3 to 3.9. The
pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride. Solutions in
contact with the plastic container can leach out certain of its chemical components in very small amounts within
the expiration period, for example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of
the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well
as by tissue culture toxicity studies.
The glucose content for the 100 mL bag is 5 g and 10 g for the 200 mL flexible container.
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2
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (mcg/mL)
After 60-minute IV Infusions q 12 h.
Time after starting the infusion
Dose
30 min.
1 hr
3 hr
6 hr
8 hr
12 hr
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th IV dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg IV dose
results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin
given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every
12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and IV Doses
Parameters
500 mg
400 mg
750 mg
400 mg
q12h, P.O.
q12h, IV
q12h, P.O.
q8h, IV
AUC (mcg•hr/mL)
13.7 a
12.7 a
31.6 b
32.9 c
Cmax (mcg/mL)
2.97
4.56
3.59
4.07
a AUC0-12h
b AUC 24h=AUC0-12h × 2
c AUC 24h=AUC0-8h × 3
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
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Metabolism
After IV administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS, WARNINGS;
PRECAUTIONS, Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg IV dose, concentrations in the urine usually exceed 200 mcg/mL
0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing. Following a
400-mg IV dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after dosing and are
usually greater than 30 mcg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an IV dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS, Geriatric Use.)
Patients with Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
Patients with Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Pediatrics
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 – 3.4 mcg/mL) and the mean AUC was
9.2 mcg*h/mL (range: 5.8 – 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable
increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were
given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range:
4.6 – 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 – 11.8 mcg/mL) in
10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8 – 32.0
mcg*h/mL) and 16.5 mcg*h/mL (range: 11.0 – 23.8 mcg*h/mL) in the respective age groups. These
values are within the range reported for adults at therapeutic doses. Based on population
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4
pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in
children is approximately 4–5 hours, and the bioavailability of the oral suspension is approximately
60%.
Drug-Drug Interactions
Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS). The
potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine,
cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and piperacillin
sodium has been evaluated. (See WARNINGS: PRECAUTIONS, Drug Interactions.)
MICROBIOLOGY
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA
replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones
occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or
drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance
to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6
.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro
and in clinical infections as described in the INDICATIONS AND USAGE section of the package
insert for CIPRO IV (ciprofloxacin for intravenous infusion).
Gram-positive bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible isolates only)
Streptococcus pyogenes
Gram-negative bacteria
Citrobacter koseri (diversus)
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
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5
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION).
The following in vitro data are available, but their clinical significance is unknown. At least 90
percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less
than or equal to the susceptible breakpoint for ciprofloxacin (<1 mcg/mL). However, the efficacy of
ciprofloxacin in treating clinical infections due to these bacteria has not been established in
adequate and well-controlled clinical trials.
Gram-positive bacteria
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
Bacillus anthracis
Gram-negative bacteria
Acinetobacter lwoffi
Aeromonas hydrophila
Edwardsiella tarda
Enterobacter aerogenes
Klebsiella oxytoca
Legionella pneumophila
Pasteurella multocida
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility
test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports
that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports
should aid the physician in selecting an antibacterial drug product for treatment.
•
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to
antimicrobial compounds. The MICs should be determined using a standardized test method (broth
and/or agar).1,3,4 The MIC values should be interpreted according to criteria provided in Table 1.
•
Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The
zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The
zone size should be determined using a standardized test method.2,3,4 This procedure uses paper
disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin.
The disc diffusion interpretive criteria are provided in Table 1.
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6
Table 1: Susceptibility Test Interpretive Criteria for Ciprofloxacin
MIC (mcg/mL)
Zone Diameter (mm)
Bacteria
S
I
R
S
I
R
Enterobacteriaceae
≤1
2
≥4
≥21
16–20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus aureus,
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus epidermidis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus saprophyticus
≤1
2
≥4
≥21
16–20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16–20
≤15
Haemophilus influenzae a
≤1
-
-
≥21
-
-
Haemophilus parainfluenzae a
≤1
-
-
≥21
-
-
Streptococcus pneumoniae
≤1
2
≥4
≥21
16–20
≤15
Streptococcus pyogenes
≤1
2
≥4
≥21
16–20
≤15
Bacillus anthracisa
≤0.25
-
-
-
-
-
S=Susceptible, I=Intermediate, and R=Resistant.
a The current absence of data on resistant isolates precludes defining any results other than “Susceptible.” If isolates
yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if
the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit
growth of the pathogen. A report of “Intermediate” indicates that the result should be considered
equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the
test should be repeated. This category implies possible clinical applicability in body sites where the drug
is physiologically concentrated or in situations where high dosage of drug can be used. This category
also provides a buffer zone that prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to
inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually
achievable at the infection site; other therapy should be selected.
•
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls
to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques
of the individuals performing the test .1,2,3,4 Standard ciprofloxacin powder should provide the
following range of MIC values noted in Table 2. For the diffusion technique using the ciprofloxacin
5 mcg disk the criteria in Table 2 should be achieved.
Table 2: Acceptable Quality Control Ranges for Ciprofloxacin
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7
INDICATIONS AND USAGE
CIPRO IV is indicated for the treatment of infections caused by susceptible isolates of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
rettgeri, Morganella morganii, Citrobacter koseri (diversus), Citrobacter freundii, Pseudomonas
aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or
vancomycin-susceptible Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae , Enterobacter cloacae,
Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or
penicillin-susceptible Streptococcus pneumoniae.* Also, Moraxella catarrhalis for the treatment of acute
exacerbations of chronic bronchitis.
*Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia
secondary to Streptococcus pneumoniae.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter
freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus,
methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas
aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by Escherichia
coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or
Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Bacteria
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03
34–42
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC 29213
0.12–0.5
-
Staphylococcus aureus ATCC 25923
-
22–30
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8
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric Patients (1 to 17 years of age)
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients
Inhalational Anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to
predict clinical benefit and provided the initial basis for approval of this indication.6 Supportive clinical
information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax
bioterror attacks of October 2001. (See also INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO IV may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also
on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and
other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components (see
DESCRIPTION).
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
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9
WARNINGS
Tendinopathy and Tendon Rupture
Fluoroquinolones, including CIPRO IV, are associated with an increased risk of tendinitis and tendon
rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of
the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the
shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of
developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney,
heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently
increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon
disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients
taking fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can
occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases
occurring up to several months after completion of therapy have been reported. CIPRO IV should be
used with caution in patients with a history of tendon disorders. CIPRO IV should be discontinued if the
patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to
rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis
Fluoroquinolones, including CIPRO IV, have neuromuscular blocking activity and may exacerbate
muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including
deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in
persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis.
(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Postmarketing
Adverse Event Reports.)
Pregnant Women
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND
LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pregnancy,
and Nursing Mothers subsections.)
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been
reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular
collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.
Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require
immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen,
intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway
management, as clinically indicated.
Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
•
Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis,
Stevens-Johnson syndrome);
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•
Vasculitis; arthralgia; myalgia; serum sickness;
•
Allergic pneumonitis;
•
Interstitial nephritis; acute renal insufficiency or failure;
•
Hepatitis; jaundice; acute hepatic necrosis or failure;
•
Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Hepatobiliary System
Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal
events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range 1-39 days), and
is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or
mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and
symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment
should be discontinued immediately (see ADVERSE REACTIONS).
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic
jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin
(see ADVERSE REACTIONS).
Theophylline
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING
CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Central Nervous System Effects
Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have
been reported in patients receiving fluoroquinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, psychotic reactions have progressed to suicidal ideations/thoughts and
self-injurious behavior such as attempted or completed suicide. These reactions may occur following
the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be
discontinued, patients should be advised to inform their healthcare provider immediately and
appropriate measures instituted. As with all fluoroquinolones, ciprofloxacin should be used with
caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to
seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of
convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other
risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug
therapy, renal dysfunction). CIPRO IV should only be used where the benefits of treatment exceed the
risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of
status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued. (See
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PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE
REACTIONS.)
Clostridium Difficile-Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including CIPRO, and may range in severity from mild diarrhea to fatal colitis. Treatment with
antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral Neuropathy
Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in
paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving
fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of CIPRO and
may be irreversible. Ciprofloxacin should be discontinued immediately if the patient experiences
symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or
other alterations in sensations including light touch, pain, temperature, position sense and vibratory
sensation.
Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in
the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to
controls, including events related to joints and/or surrounding tissues, has been observed. (See
ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Prolongation of the QT Interval
Some fluoroquinolones, including CIPRO IV, have been associated with prolongation of the QT
interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes
have been spontaneously reported during postmarketing surveillance in patients receiving
fluoroquinolones, including ciprofloxacin. CIPRO IV should be avoided in patients with known
prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example,
congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalemia or
hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and
patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic
agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics).. Elderly
patients may also be more susceptible to drug-associated effects on the QT interval. (See
PRECAUTIONS, Drug Interactions and Geriatric Use.)
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Cytochrome P450 (CYP450)
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of
ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline,
methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma
concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic
side effects of the coadministered drug. (See PRECAUTIONS, Drug Interactions.)
PRECAUTIONS
General
INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW INFUSION
OVER A PERIOD OF 60 MINUTES. Local IV site reactions have been reported with the intravenous
administration of ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less
or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including:
nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See Information for Patients, and
Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in
the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment
Alteration of the dosage regimen is necessary for patients with impairment of renal function. (See
DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as
exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema)
involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the
forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light
exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy
should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS, Postmarketing
Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant
bacteria.
Information For Patients
Patients should be advised:
•
To contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO IV treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
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13
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
•
That fluoroquinolones like CIPRO IV may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
•
That antibacterial drugs including CIPRO IV should only be used to treat bacterial infections. They do
not treat viral infections (for example, the common cold). When CIPRO IV is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the
full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable by CIPRO IV or other
antibacterial drugs in the future.
•
That ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to
discontinue the drug at the first sign of a skin rash or other allergic reaction.
•
That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
•
That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react
to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness
or coordination.
•
That ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
•
That ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of caffeine
accumulation when products containing caffeine are consumed while taking ciprofloxacin.
•
That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may
occur soon after initiation of therapy and may be irreversible If symptoms of peripheral neuropathy
including pain, burning, tingling, numbness and/or weakness develop, patients should immediately
discontinue Cipro and contact their physician.
•
That convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to notify
their physician before taking this drug if there is a history of this condition.
•
That ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
•
That diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
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Drug Interactions
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly
increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500
mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated.
Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
Theophylline
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to
elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in
increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be
avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Other Xanthine Derivatives
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life. On
concurrent administration of ciprofloxacin and caffeine or pentoxifylline containing products, elevated
serum concentrations of these xanthine derivatives were reported.
Cyclosporine
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Phenytoin
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant
ciprofloxacin. To avoid the loss of seizure control associated with decreased phenytoin levels, and to
prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients
receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration
measurements, is recommended during and shortly after co-administration of CIPRO IV with
phenytoin.
Oral Antidiabetic Agents
Hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas
(for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of
the oral antidiabetic agent (see ADVERSE REACTIONS). The concomitant administration of
ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia. Fatalities have
been reported.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were
given concomitantly.
Oral Anti-Coagulants
Simultaneous administration of ciprofloxacin with an oral anticoagulant may augment the effect of the
anticoagulant. The risk may vary with the underlying infection, age and general status of the patient so
that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult
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15
to assess. Prothrombin time and INR should be monitored frequently during and shortly after
co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Probenecid
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of
ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Methotrexate
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin
potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate
associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when
concomitant ciprofloxacin therapy is indicated.
Duloxetine
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the
CYP450 1A2 isozyme such as fluvoxamine, may result in an a 5-fold increase of in mean AUC and a
2.5-fold increase in mean Cmax of duloxetine. Although no clinical data are available on a possible
interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.
NSAIDs
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Ropinirole
In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole
once daily with 500 mg ciprofloxacin twice-daily, the mean Cmax and mean AUC of ropinirole were
increased by 60% and 84%, respectively. Monitoring for ropinirole-related side effects and appropriate
dose adjustment of ropinirole is recommended during and shortly after co-administration with
ciprofloxacin. (See Warnings, Cytochrome P450.)
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg
ciprofloxacin twice daily, resulted in an increase of lidocaine Cmax and AUC by 12% and 26%,
respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible
interaction with ciprofloxacin and an increase in side effects related to lidocaine may occur upon
concomitant administration.
Clozapine
Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days,
serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%,
respectively. Careful monitoring of clozapine associated adverse effects and and appropriate adjustment
of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. (See
WARNINGS.)
Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg
ciprofloxacin to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased
approximately two-fold. Therefore, sildenafil should be used with caution when co-administered with
ciprofloxacin.
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Drugs known to prolong QT interval
Precaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the
QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides,
antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see PRECAUTIONS,
Geriatric Use)
Piperacillin Sodium
Following infusion of 400 mg IV ciprofloxacin every eight hours in combination with 50 mg/kg IV piperacillin
sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 mcg/mL ½ hour and 1.18 mcg/mL
between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Eight in vitro mutagenicity tests have been conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5-times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.5
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
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Pregnancy
Teratogenic Effects. Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Ciprofloxacin should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS –
the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to
state that there is no risk.9
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.6 In utero exposure to fluo-
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).11 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to
ciprofloxacin during pregnancy.9,10 However, these small postmarketing epidemiology studies, of which most
experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to
permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their
developing fetuses.
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is
unknown. Because of the potential risk of serious adverse reactions (including articular damage) in
infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing
joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.)
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18
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin IV 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime IV 50 mg/kg/dose q8h and tobramycin IV 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture
when being treated with a fluoroquinolone such as CIPRO IV This risk is further increased in patients
receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles,
hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases
occurring up to several months after fluoroquinolone treatment have been reported. Caution should be
used when prescribing CIPRO IV to elderly patients especially those on corticosteroids. Patients should
be informed of this potential side effect and advised to discontinue CIPRO IV and contact their
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19
healthcare provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning,
WARNINGS, and ADVERSE REACTIONS/Postmarketing Adverse Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but greater sensitivity of some older
individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted
by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.
No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function.
However, since some older individuals experience reduced renal function by virtue of their advanced
age, care should be taken in dose selection for elderly patients, and renal function monitoring may be
useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore,
precaution should be taken when using CIPRO with concomitant drugs that can result in prolongation of
the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for
torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia).
ADVERSE REACTIONS
Adverse Reactions in Adult Patients
During clinical investigations with oral and parenteral ciprofloxacin, 49,038 patients received courses
of the drug. Most of the adverse events reported were described as only mild or moderate in severity,
abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued
because of an adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local IV site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local IV site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures (including status epilepticus), grand mal
convulsion, paranoia, toxic psychosis, depression (potentially culminating in self-injurious behavior,
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20
such as suicidal ideations/thoughts and attempted or completed suicide), dysphasia, phobia,
depersonalization, manic reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness,
lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness, irritability,
malaise, lethargy, abnormal gait
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase, hyperglycemia, hypoglycemia
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis, muscle weakness
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (IV and IV/P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients
Ciprofloxacin, administered IV and /or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in
the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
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21
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received IV or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI
performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome
secondary to sports activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient
recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
Ciprofloxacin
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval*
(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months
1/36 (2.8%)
0/41
≥ 2 years < 6 years
5/124 (4.0%)
3/118 (2.5%)
≥ 6 years < 12 years
18/143 (12.6%)
12/153 (7.8%)
≥ 12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval*
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
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Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients.
Postmarketing Adverse Event Reports
The following adverse events have been reported from worldwide marketing experience with
fluoroquinolones, including ciprofloxacin. Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. Decisions to include these events in labeling are typically based on
one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3)
strength of causal connection to the drug.
Acute generalized exanthematous pustulosis (AGEP), Agitation, agranulocytosis, albuminuria,
anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia,
dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation
(blood), hemolytic anemia, hepatic failure (including fatal cases), hepatic necrosis, hyperesthesia,
hypertonia, hypesthesia, hypotension (postural) International Normalized Ratio (INR) increased (in
patients treated with Vitamin K antagonists), jaundice, marrow depression (life threatening),
methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, exacerbation of
myasthenia gravis, myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal
outcome), peripheral neuropathy that may be irreversable, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, polyneuropathy, potassium elevation (serum), prothrombin
time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis
symptoms may occur during or after antimicrobial treatment), psychosis (toxic), QT prolongation, renal
calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture,
torsade de pointes, toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum),
twitching, vaginal candidiasis, vasculitis, and ventricular arrhythmia. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also Inhalational Anthrax,
Additional Information).
Adverse Laboratory Changes
The most frequently reported changes in laboratory parameters with intravenous ciprofloxacin therapy,
without regard to drug relationship are listed below:
Hepatic—elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin
Hematologic—elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal—elevations of serum creatinine, BUN, and uric acid
Other—elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(gGT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
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23
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive treatment,
including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria.
Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is removed
from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATION
Adults
CIPRO IV should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO IV
for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity
and nature of the infection, the susceptibility of the causative microorganism, the integrity of the
patient’s host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
Frequency
Usual Duration
Urinary Tract
Mild/Moderate
200 mg
q12h
7-14 Days
Severe/Complicated
400 mg
q12h (or q 8h)
7-14 Days
Lower
Mild/Moderate
400 mg
q12h
7-14 Days
Respiratory Tract
Severe/Complicated
400 mg
q8h
7-14 Days
Nosocomial
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Pneumonia
Skin and
Mild/Moderate
400 mg
q12h
7-14 Days
Skin Structure
Severe/Complicated
400 mg
q8h
7-14 Days
Bone and Joint
Mild/Moderate
400 mg
q12h
≥ 4-6 Weeks
Severe/Complicated
400 mg
q8h
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Mild/Moderate
400 mg
q12h
28 Days
Prostatitis
Empirical Therapy
Severe
in
Febrile Neutropenic
Ciprofloxacin
400 mg
q8h
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24
Patients
+
7-14 Days
Piperacillin
50 mg/kg
q4h
Not to exceed
24 g/day
Inhalational anthrax
400 mg
q12h
60 Days
(post-exposure)**
*Used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in
various human populations, see Inhalational Anthrax, Additional Information). Total duration of
ciprofloxacin administration (IV or oral) for inhalational anthrax (post-exposure) is 60 days.
CIPRO IV should be administered by intravenous infusion over a period of 60 minutes.
Conversion of IV to Oral Dosing in Adults
CIPRO Tablets and CIPRO Oral Suspension for oral administration are available. Parenteral therapy may
be switched to oral CIPRO when the condition warrants, at the discretion of the physician. (See
CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO IV Dosage
250 mg Tablet q 12 h
200 mg IV q 12 h
500 mg Tablet q 12 h
400 mg IV q 12 h
750 mg Tablet q 12 h
400 mg IV q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended for patients with severe renal
dysfunction. The following table provides dosage guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
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Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
Pediatrics
CIPRO IV should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., IV or oral) for complicated urinary tract infection or pyelonephritis
should be determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to
severe infection were initiated on 6 to 10 mg/kg IV every 8 hours and allowed to switch to oral therapy (10 to
20 mg/kg every 12 hours), at the discretion of the physician.
PEDIATRIC DOSAGE GUIDELINES
Infection
Route of
Administration
Dose
(mg/kg)
Frequency
Total
Duration
Complicated
Urinary Tract
or
Pyelonephritis
(patients from
1 to 17 years of
age)
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 8
hours
10-21 days*
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
Every 12
hours
Inhalational
Anthrax
(Post-Exposure)
**
Intravenous
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
60 days
Oral
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
** Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.6 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
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26
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO IV for Administration
Vials (Injection Concentrate)
THIS PREPARATION MUST BE DILUTED BEFORE USE. The intravenous dose should be prepared by
aseptically withdrawing the concentrate from the vial of CIPRO IV This should be diluted with a
suitable intravenous solution to a final concentration of 1–2 mg/mL. (See Compatibility and Stability.)
The resulting solution should be infused over a period of 60 minutes by direct infusion or through a Y-type
intravenous infusion set which may already be in place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO IV If the concomitant use of
CIPRO IV and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers
CIPRO IV is also available as a 0.2% premixed solution in 5% dextrose in flexible containers of 100 mL
or 200 mL. The solutions in flexible containers do not need to be diluted and may be infused as
described above.
Compatibility and Stability
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO IV (ciprofloxacin) is available in a clear, colorless to slightly yellowish solution. CIPRO IV is
available in a 400 mg strength. The premixed solution is supplied in latex-free flexible containers as
follows:
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany.
SIZE
STRENGTH
NDC NUMBER
200 mL 5% Dextrose
400 mg, 0.2%
50419-759-01
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27
STORAGE
Flexible Container: Store between 5 – 25ºC (41 – 77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile
dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused
degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg
ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma
AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology
after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose
based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not
associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study,
removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions,
which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically
acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon
mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
Inhalational Anthrax
Additional Information
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12
This label may not be the latest approved by FDA.
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28
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 mcg/mL and trough concentrations range from 0.09 to 0.26 mcg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.6
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 mcg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 mcg/mL5. Mortality due to
anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours
post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.8
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of ciprofloxacin, 400 mg IV q 8h, in combination with piperacillin
sodium, 50 mg/kg IV q 4h, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to those of
tobramycin, 2 mg/kg IV q 8h, in combination with piperacillin sodium, 50 mg/kg IV q 4h.
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29
Clinical response rates observed in this study were as follows:
Outcomes
Ciprofloxacin/Piperacillin
Tobramycin/Piperacillin
N = 233
N = 237
Success (%)
Success (%)
Clinical Resolution of
63
(27.0%)
52
(21.9%)
Initial Febrile Episode with
No Modifications of
Empirical Regimen*
Clinical Resolution of
187
(80.3%)
185
(78.1%)
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
Overall Survival
224
(96.1%)
223
(94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered IV and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
Post-Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
at 5 to 9 Days Post-Treatment*
84.4% (178/211)
78.3% (181/231)
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30
95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. Clinical Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically; Approved Standard – 9th Edition. CLSI Document M7-A9, CLSI,
950 West Valley Rd., Suite 2500, Wayne, PA, January, 2012.
2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved
Standard – 11th Edition. CLSI Document M2-A10, CLSI, Wayne, PA, January, 2012.
3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational
Supplement. CLSI Document M100 S22, January 2012.
4. CLSI. Methods for Antimicrobial Dilution and Disk Susceptbility Testing of Infrequently Isolated or
Fastidious Bacteria; Approved Guideline – 2nd Edition. CLSI Document M45 A2, January 2010.
5. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
6. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
7. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
8. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
9. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
10. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
11. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
TABLETS
CIPRO® (Sip-row)
(ciprofloxacin)
ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® IV (Sip-row)
(ciprofloxacin)
For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® before you start taking it and
each time you get a refill. There may be new information. This Medication Guide does
not take the place of talking to your healthcare provider about your medical condition
or your treatment.
What is the most important information I should know about CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO can cause
side effects that may be serious or even cause death. If you get any of the following
serious side effects, get medical help right away. Talk with your healthcare provider
about whether you should continue to take CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis)
• Tendon problems can happen in people of all ages who take CIPRO. Tendons
are tough cords of tissue that connect muscles to bones. Symptoms of tendon
problems may include:
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
• The risk of getting tendon problems while you take CIPRO is higher if you:
• Are over 60 years of age
• Are taking steroids (corticosteroids)
• Have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO. Other reasons that can increase your risk of
tendon problems can include:
• Physical activity or exercise
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• Kidney failure
• Tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling
or inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled
out by your healthcare provider. Avoid exercise and using the affected area. The most
common area of pain and swelling is the Achilles tendon at the back of your ankle. This
can also happen with other tendons.
• Talk to your healthcare provider about the risk of tendon rupture with continued
use of CIPRO. You may need a different antibiotic that is not a fluoroquinolone to treat
your infection.
• Tendon rupture can happen while you are taking or after you have finished
taking CIPRO. Tendon ruptures have happened up to several months after patients
have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms
of a tendon rupture:
• Hear or feel a snap or pop in a tendon area
• Bruising right after an injury in a tendon area
• Unable to move the affected area or bear weight
2. Worsening of myasthenia gravis (a disease which causes muscle weakness).
Fluoroquinolones like CIPRO may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Call your healthcare provider
right away if you have any worsening muscle weakness or breathing problems.
See the section “What are the possible side effects of CIPRO?” for more
information about side effects.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused
by certain germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or
tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO.
CIPRO should not be used as the first choice of antibiotic medicine in children under
18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO IV should not be used in children
under 18 years old, except to treat specific serious infections, such as complicated
urinary tract infections and to prevent anthrax disease after breathing the anthrax
bacteria germ (inhalational exposure). It is not known if CIPRO XR is safe and works in
children under 18 years of age.
Sometimes infections are caused by viruses rather than by bacteria. Examples include
viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics,
including CIPRO, do not kill viruses.
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Call your healthcare provider if you think your condition is not getting better while you
are taking CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
• Have ever had a severe allergic reaction to an antibiotic known as a
fluoroquinolone, or are allergic to any of the ingredients in CIPRO. Ask your
healthcare provider if you are not sure. See the list of ingredients in CIPRO at the
end of this Medication Guide.
• Also take a medicine called tizanidine (Zanaflex®). Serious side effects from
tizanidine are likely to happen.
What should I tell my healthcare provider before taking CIPRO?
See “What is the most important information I should know about CIPRO?”.
Tell your healthcare provider about all your medical conditions, including if
you:
• Have tendon problems.
• Have a disease that causes muscle weakness (myasthenia gravis).
• Have central nervous system problems (such as epilepsy).
• Have nerve problems.
• Have or anyone in your family has an irregular heartbeat, especially a condition
called “QT prolongation”.
• Have a history of seizures.
• Have kidney problems. You may need a lower dose of CIPRO if your kidneys do
not work well.
• Have rheumatoid arthritis (RA) or other history of joint problems.
• Have trouble swallowing pills.
• Are pregnant or planning to become pregnant. It is not known if CIPRO will harm
your unborn child.
• Are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You
and your healthcare provider should decide whether you will take CIPRO or
breast-feed.
Tell your healthcare provider about all the medicines you take, including
prescription and non-prescription medicines, vitamins and herbal and dietary
supplements. CIPRO and other medicines can affect each other causing side effects.
Especially tell your healthcare provider if you take:
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• An NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for
pain relief are NSAIDs. Taking an NSAID while you take CIPRO or other
fluoroquinolones may increase your risk of central nervous system effects and
seizures. See "What are the possible side effects of CIPRO?."
• A blood thinner (such as warfarin, Coumadin®, Jantoven®).
• Tizanidine (Zanaflex®). You should not take CIPRO if you are already taking
tizanidine. See “Who should not take CIPRO?”.
• Theophylline (such as Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®).
• Glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the
possible side effects of CIPRO?”.
• Phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended
Phenytoin Sodium®, Prompt Phenytoin Sodium®, Phenytek®).
• Products that contain caffeine.
• A medicine to control your heart rate or rhythm (antiarrhythmics) See “What are
the possible side effects of CIPRO?”.
• An anti-psychotic medicine.
• A tricyclic antidepressant.
• A water pill (diuretic).
• A steroid medicine. Corticosteroids taken by mouth or by injection may increase
the chance of tendon injury. See “What is the most important information I
should know about CIPRO?”.
• Methotrexate (Trexall®).
• Probenecid (Probalan®, Col-probenecid®).
• Metoclopromide (Reglan®, Reglan ODT®).
• Ropinirole (Requip®).
• Lidocaine (Xylocaine® intravenous infusion).
• Clozapine (Clozaril®, Fazaclo® ODT®).
• Pentoxifylline (Trental®).
• Sildenafil (Viagra®, Revatio®).
• Cyclosporine (Gengraf®, Neoral®, Sandimmune®, Sangcya®).
• Omeprazole.
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from
working correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before
or 6 hours after taking these products:
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• An antacid, multivitamin, or other product that has magnesium, calcium,
aluminum, iron, or zinc.
• Sucralfate (Carafate®).
• Didanosine (Videx®, Videx EC®).
Ask your healthcare provider if you are not sure if any of your medicines are listed
above.
Know the medicines you take. Keep a list of your medicines and show it to your
healthcare provider and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day.
Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your
healthcare provider if you can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time
each day. Shake the CIPRO Oral Suspension bottle well each time before use for
about 15 seconds to make sure the suspension is mixed well. Close the bottle
completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the
tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if
you cannot swallow the tablet whole.
• CIPRO IV is given to you by intravenous (IV) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or
calcium-fortified juices alone, but may be taken with a meal that contains these
products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until
you finish your prescribed treatment, unless:
• You have tendon effects (see “What is the most important information I should
know about CIPRO?”),
• You have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
• Your healthcare provider tells you to stop.
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36
This will help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic
medicines may not work in the future.
• If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you
remember. Do not take two doses at the same time, and do not take more than two
doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take
more than one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO IV
after being exposed to anthrax:
CIPRO Tablets, Oral Suspension and IV has been approved to lessen the chance of
getting anthrax disease or worsening of the disease after you are exposed to the
anthrax bacteria germ.
Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking
CIPRO without talking with your healthcare provider. If you stop taking CIPRO too
soon, it may not keep you from getting the anthrax disease.
Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or IV
When taking your CIPRO to prevent anthrax infection, you and your healthcare
provider should talk about whether the risks of stopping CIPRO too soon are more
important than the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets,
Oral Suspension or IV for anthrax are more important than the risks.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery,
or do other activities that require mental alertness or coordination until you know
how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can
make your skin sensitive to the sun (photosensitivity) and the light from sunlamps
and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If
you get any of these symptoms while taking CIPRO, call your healthcare provider
right away. You should use a sunscreen and wear a hat and clothes that cover your
skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See
“What is the most important information I should know about CIPRO?”
Other serious side effects of CIPRO include:
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37
• Theophylline
You may have serious seizure and breathing problems when you take theophylline
with CIPRO. These problems may lead to death. Get emergency help right away if
you have seizures or trouble breathing.
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics
including CIPRO. Tell your healthcare provider if you have a history of seizures.
Ask your healthcare provider whether taking CIPRO will change your risk of having
a seizure.
Central Nervous System (CNS) side effects may happen as soon as after taking
the first dose of CIPRO. Talk to your healthcare provider right away if you get any of
these side effects, or other changes in mood or behavior:
• Feel dizzy
• Seizures
• Hear voices, see things, or sense things that are not there (hallucinations)
• Feel restless
• Tremors
• Feel anxious or nervous
• Confusion
• Depression
• Trouble sleeping
• Nightmares
• Feel more suspicious (paranoia)
• Suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions, including death, can happen in people taking fluoroquinolones,
including CIPRO, even after only one dose. Stop taking CIPRO and get emergency
medical help right away if you get any of the following symptoms of a severe
allergic reaction:
• Hives.
• Trouble breathing or swallowing.
• Swelling of the lips, tongue, face.
• Throat tightness, hoarseness.
• Rapid heartbeat.
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38
• Faint.
• Yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare
provider right away if you get yellowing of your skin or white part of your eyes, or
if you have dark urine. These can be signs of a serious reaction to CIPRO (a
liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop
taking CIPRO at the first sign of a skin rash and call your healthcare provider. Skin
rash may be a sign of a more serious reaction to CIPRO.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a
fast or irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem
known as prolongation of the QT interval. This condition can cause an abnormal
heartbeat and can be very dangerous. The chances of this event are higher in
people:
• Who are elderly
• With a family history of prolonged QT interval
• With low blood potassium (hypokalemia)
• Who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO.
Call your healthcare provider right away if you get watery diarrhea, diarrhea that
does not go away, or bloody stools. You may have stomach cramps and a fever.
Pseudomembranous colitis can happen 2 or more months after you have finished
your antibiotic.
• Changes in sensation and nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Stop CIPRO and talk with your healthcare
provider right away if you get any of the following symptoms of peripheral
neuropathy in your arms, hands, legs, or feet:
• Pain
• Burning
• Tingling
• Numbness
• Weakness
The nerve damage may be permanent..
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral
anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can
get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your
healthcare provider if you get low blood sugar with CIPRO. Your antibiotic medicine
may need to be changed.
• Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking
CIPRO?”.
• Joint Problems
Increased chance of problems with joints and tissues around joints in children
under 18 years old. Tell your child’s healthcare provider if your child has any joint
problems during or after treatment with CIPRO.
The most common side effects of CIPRO include:
• Nausea
• Diarrhea
• Changes in liver function tests
• Vomiting
• Rash
• Vaginal yeast infection
• Pain or discomfort in the abdomen
• Headache
These are not all the possible side effects of CIPRO. Tell your healthcare provider
about any side effect that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be
safely thrown away
• CIPRO XR
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use CIPRO for a condition for which it is not prescribed. Do
not give CIPRO to other people, even if they have the same symptoms that you have.
It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If
you would like more information about CIPRO, talk with your healthcare provider. You
can ask your healthcare provider or pharmacist for information about CIPRO that is
written for healthcare professionals. For more information call 1-888-84 BAYER
(1-888-842-2937).
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and
polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following
compositions: Microcapsules–ciprofloxacin, povidone, methacrylic acid
copolymer, hypromellose, magnesium stearate, and Polysorbate 20. Diluent–
medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate,
polyethylene glycol, silica colloidal anhydrous, succinic acid, and titanium
dioxide.
• CIPRO IV:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for
pH adjustment
Revised July 2013
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
Manufactured in Germany
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
07/13
©2013 Bayer HealthCare Pharmaceuticals Inc.
6708801
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:11.241377
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019857s062lbl.pdf', 'application_number': 19857, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
11,796
|
1
CIPRO® (ciprofloxacin hydrochloride) TABLETS
1
CIPRO® (ciprofloxacin) 5% and 10% ORAL SUSPENSION
2
3
PZXXXXXX
8/29/00
4
5
DESCRIPTION
6
CIPRO® (ciprofloxacin hydrochloride) Tablets and CIPRO® (ciprofloxacin) Oral
7
Suspension are synthetic broad spectrum antimicrobial agents for oral
8
administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the
9
monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-
10
(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow
11
crystalline substance with a molecular weight of 385.8. Its empirical formula is
12
C17H18FN3O3
lHCllH2O and its chemical structure is as follows:
13
14
[STRUCTURE]
15
16
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-
17
quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular
18
weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its
19
chemical structure is as follows:
20
21
[STRUCTURE]
22
23
Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-
24
position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-
25
position.
26
27
CIPRO® film-coated tablets are available in 100-mg, 250-mg, 500-mg and 750-mg
28
(ciprofloxacin equivalent) strengths. The inactive ingredients are starch,
29
microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate,
30
hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and water.
31
32
Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and
33
10% (10 g ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a
34
white to slightly yellowish suspension with strawberry flavor which may contain
35
yellow-orange droplets. It is composed of ciprofloxacin microcapsules and diluent
36
which are mixed prior to dispensing (See instructions for USE/HANDLING). The
37
components of the suspension have the following compositions:
38
39
Microcapsules - ciprofloxacin, polyvinylpyrrolidone, methacrylic acid copolymer,
40
hydroxypropyl methylcellulose, magnesium stearate, and Polysorbate 20.
41
Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.
42
43
44
CLINICAL PHARMACOLOGY
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
46
Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the
47
gastrointestinal tract after oral administration. The absolute bioavailability is
48
approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin
49
maximum serum concentrations and area under the curve are shown in the chart for
50
the 250-mg to 1000-mg dose range.
51
52
Maximum
Area
53
Dose
Serum Concentration
Under Curve (AUC)
54
(mg)
(µµg/mL)
(µµg.hr/mL)
55
56
250
1.2
4.8
57
500
2.4
11.6
58
750
4.3
20.2
59
1000
5.4
30.8
60
61
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean
62
concentrations 12 hours after dosing with 250, 500, or 750-mg are 0.1, 0.2, and 0.4
63
mg/mL, respectively. Serum concentrations increase proportionately with doses up
64
to 1000-mg.
65
66
A 500-mg oral dose given every 12 hours has been shown to produce an area
67
under the serum concentration time curve (AUC) equivalent to that produced by an
68
intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.
69
A 750-mg oral dose given every 12 hours has been shown to produce an AUC at
70
steady-state equivalent to that produced by an intravenous infusion of 400 mg given
71
over 60 minutes every 8 hours. A 750-mg oral dose results in a Cmax similar to that
72
observed with a 400-mg I.V. dose. A 250-mg oral dose given every 12 hours
73
produces an AUC equivalent to that produced by an infusion of 200 mg
74
ciprofloxacin given every 12 hours.
75
76
Steady-state Pharmacokinetic Parameter
77
Following Multiple Oral and I.V. Doses
78
79
Parameters 500 mg
400 mg
750 mg
400 mg
80
q12h, P.O.
q12h, I.V. q12h, P.O.
q8h, I.V.
81
82
AUC (µglhr/mL) 13.7a
12.7a 31.6b 32.9c
83
Cmax(µg/mL
2.97
4.56 3.59
4.07
84
85
aAUC 0-12h bAUC 24h=AUC0-12hx2 cAUC 24h=AUC0-8hx3
86
87
88
89
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
The serum elimination half-life in subjects with normal renal function is approximately
90
4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the
91
urine as unchanged drug. After a 250-mg oral dose, urine concentrations of
92
ciprofloxacin usually exceed 200 µg/mL during the first two hours and are
93
approximately 30 µg/mL at 8 to 12 hours after dosing. The urinary excretion of
94
ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance
95
of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal
96
glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would
97
seem to play a significant role in its elimination. Co-administration of probenecid
98
with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal
99
clearance and a 50% increase in its concentration in the systemic circulation.
100
Although bile concentrations of ciprofloxacin are several fold higher than serum
101
concentrations after oral dosing, only a small amount of the dose administered is
102
recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is
103
recovered from the bile in the form of metabolites. Approximately 20 to 35% of an
104
oral dose is recovered from the feces within 5 days after dosing. This may arise
105
from either biliary clearance or transintestinal elimination. Four metabolites have
106
been identified in human urine which together account for approximately 15% of an
107
oral dose. The metabolites have antimicrobial activity, but are less active than
108
unchanged ciprofloxacin.
109
110
With oral administration, a 500-mg dose, given as 10 mL of the 5% CIPRO ®
111
Suspension (containing 250-mg ciprofloxacin/5mL) is bioequivalent to the 500-mg
112
tablet. A 10 mL volume of the 5% CIPRO ® Suspension (containing 250-mg
113
ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO ®
114
Suspension (containing 500-mg ciprofloxacin/5mL).
115
116
When CIPRO ® Tablet is given concomitantly with food, there is a delay in the
117
absorption of the drug, resulting in peak concentrations that occur closer to 2 hours
118
after dosing rather than 1 hour whereas there is no delay observed when CIPRO ®
119
Suspension is given with food. The overall absorption of CIPRO ® Tablet or CIPRO
120
® Suspension, however, is not substantially affected. The pharmacokinetics of
121
ciprofloxacin given as the suspension are also not affected by food. Concurrent
122
administration of antacids containing magnesium hydroxide or aluminum hydroxide
123
may reduce the bioavailability of ciprofloxacin by as much as 90%. (See
124
PRECAUTIONS.)
125
126
The serum concentrations of ciprofloxacin and metronidazole were not altered when
127
these two drugs were given concomitantly.
128
129
Concomitant administration of ciprofloxacin with theophylline decreases the
130
clearance of theophylline resulting in elevated serum theophylline levels and
131
increased risk of a patient development CNS or other adverse reactions.
132
Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
133
paraxanthine after caffeine administration. (See PRECAUTIONS.)
134
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
135
Pharmacokinetic studies of the oral (single dose) and intravenous (single and
136
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of
137
ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
138
adults. Although the Cmax is increased 16-40%, the increase in mean AUC is
139
approximately 30%, and can be at least partially attributed to decreased renal
140
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the
141
elderly. These differences are not considered clinically significant. (See
142
PRECAUTIONS: Geriatric Use.)
143
144
In patients with reduced renal function, the half-life of ciprofloxacin is slightly
145
prolonged. Dosage adjustments may be required. (See DOSAGE AND
146
ADMINISTRATION.)
147
148
In preliminary studies in patients with stable chronic liver cirrhosis, no significant
149
changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of
150
ciprofloxacin in patients with acute hepatic insufficiency, however, have not been
151
fully elucidated.
152
153
The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be
154
high enough to cause significant protein binding interactions with other drugs.
155
156
After oral administration, ciprofloxacin is widely distributed throughout the body.
157
Tissue concentrations often exceed serum concentrations in both men and women,
158
particularly in genital tissue including the prostate. Ciprofloxacin is present in active
159
form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum,
160
skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin
161
has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug
162
diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are
163
generally less than 10% of peak serum concentrations. Low levels of the drug have
164
been detected in the aqueous and vitreous humors of the eye.
165
166
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-
167
negative and gram-positive organisms. The bactericidal action of ciprofloxacin
168
results from interference with the enzyme DNA gyrase which is needed for the
169
synthesis of bacterial DNA. Ciprofloxacin does not cross-react with other
170
antimicrobial agents such as beta-lactams or aminoglycosides; therefore,
171
organisms resistant to these drugs may be susceptible to ciprofloxacin. In vitro
172
studies have shown that additive activity often results when ciprofloxacin is
173
combined with other antimicrobial agents such as beta-lactams, aminoglycosides,
174
clindamycin, or metronidazole. Synergy has been reported particularly with the
175
combination of ciprofloxacin and a beta-lactam; antagonism is observed only rarely.
176
177
Ciprofloxacin has been shown to be active against most strains of the following
178
microorganisms, both in vitro and in clinical infections as described in the
179
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
INDICATIONS AND USAGE section of the package insert for CIPRO®
180
(ciprofloxacin hydrochloride) Tablets and CIPRO® (ciprofloxacin) 5% and 10% Oral
181
Suspension.
182
183
Aerobic gram-positive microorganisms
184
Enterococcus faecalis (Many strains are only moderately susceptible.)
185
Staphylococcus aureus (methicillin susceptible)
186
Staphylococcus epidermidis
187
Staphylococcus saprophyticus
188
Streptococcus pneumoniae
189
Streptococcus pyogenes
190
191
192
Aerobic gram-negative microorganisms
193
Campylobacter jejuni
Proteus mirabilis
194
Citrobacter diversus
Proteus vulgaris
195
Citrobacter freundii
Providencia rettgeri
196
Enterobacter cloacae
Providencia stuartii
197
Escherichia coli
Pseudomonas aeruginosa
198
Haemophilus influenzae
Salmonella typhi
199
Haemophilus parainfluenzae
Serratia marcescens
200
Klebsiella pneumoniae
Shigella boydii
201
Moraxella catarrhalis
Shigella dysenteriae
202
Morganella morganii
Shigella flexneri
203
Neisseria gonorrhoeae
Shigella sonnei
204
205
206
Ciprofloxacin has been shown to be active against most strains of the following
207
microorganisms, both in vitro and in clinical infections as described in the
208
INDICATIONS AND USAGE section of the package insert for CIPRO® I.V.
209
(ciprofloxacin for intravenous infusion).
210
211
Aerobic gram-positive microorganisms
212
Enterococcus faecalis (Many strains are only moderately susceptible.)
213
Staphylococcus aureus (methicillin susceptible)
214
Staphylococcus epidermidis
215
Staphylococcus saprophyticus
216
Streptococcus pneumoniae
217
Streptococcus pyogenes
218
219
Aerobic gram-negative microorganisms
220
Citrobacter diversus
Morganella morganii
221
Citrobacter freundii
Proteus mirabilis
222
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Enterobacter cloacae
Proteus vulgaris
223
Escherichia coli
Providencia rettgeri
224
Haemophilus influenzae
Providencia stuartii
225
Haemophilus parainfluenzae
Pseudomonas aeruginosa
226
Klebsiella pneumoniae
Serratia marcescens
227
228
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro
229
and by use of serum levels as a surrogate marker (see INDICATIONS AND
230
USAGE and INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
231
232
The following in vitro data are available, but their clinical significance is
233
unknown.
234
235
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL
236
or less against most (>90%) strains of the following microorganisms; however, the
237
safety and effectiveness of ciprofloxacin in treating clinical infections due to these
238
microorganisms have not been established in adequate and well-controlled clinical
239
trials.
240
241
Aerobic gram-positive microorganisms
242
Staphylococcus haemolyticus
243
Staphylococcus hominis
244
245
Aerobic gram-negative microorganisms
246
Acinetobacter Iwoffi
Pasteurella multocida
247
Aeromonas hydrophila
Salmonella enteritidis
248
Edwardsiella tarda
Vibrio cholerae
249
Enterobacter aerogenes
Vibrio parahaemolyticus
250
Klebsiella oxytoca
Vibrio vulnificus
251
Legionella pneumophila
Yersinia enterocolitica
252
253
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas
254
maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including
255
Bacteroides fragilis and Clostridium difficile.
256
257
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
258
little effect when tested in vitro. The minimal bactericidal concentration (MBC)
259
generally does not exceed the minimal inhibitory concentration (MIC) by more than a
260
factor of 2. Resistance to ciprofloxacin in vitro develops slowly (multiple-step
261
mutation).
262
263
Susceptibility Tests
264
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Dilution Techniques: Quantitative methods are used to determine antimicrobial
265
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
266
susceptibility of bacteria to antimicrobial compounds. The MICs should be
267
determined using a standardized procedure. Standardized procedures are based
268
on a dilution method1 (broth or agar) or equivalent with standardized inoculum
269
concentrations and standardized concentrations of ciprofloxacin powder. The MIC
270
values should be interpreted according to the following criteria:
271
272
For testing aerobic microorganisms other than Haemophilus influenzae,
273
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
274
275
MIC (µµg/mL)
Interpretation
276
< 1
Susceptible (S)
277
2
Intermediate (I)
278
> 4
Resistant (R)
279
280
aThese interpretive standards are applicable only to broth microdilution
281
susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with
282
2-5% lysed horse blood.
283
284
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
285
286
MIC (µµg/mL) Interpretation
287
< 1
Susceptible (S)
288
289
b This interpretive standard is applicable only to broth microdilution susceptibility
290
tests with Haemophilus influenzae and Haemophilus parainfluenzae using
291
Haemophilus Test Medium¹.
292
293
The current absence of data on resistant strains precludes defining any results other
294
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible “
295
category should be submitted to a reference laboratory for further testing.
296
297
For testing Neisseria gonorrhoeae
c:
298
299
MIC (µµg/mL) Interpretation
300
< 0.06
Susceptible (S)
301
302
c This interpretive standard is applicable only to agar dilution test with GC agar base
303
and 1% defined growth supplement.
304
305
The current absence of data on resistant strains precludes defining any results other
306
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible”
307
category should be submitted to a reference laboratory for further testing.
308
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
309
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
310
antimicrobial compound in the blood reaches the concentrations usually achievable.
311
A report of “Intermediate” indicates that the result should be considered equivocal,
312
and, if the microorganism is not fully susceptible to alternative, clinically feasible
313
drugs, the test should be repeated. This category implies possible clinical
314
applicability in body sites where the drug is physiologically concentrated or in
315
situations where high dosage of drug can be used. This category also provides a
316
buffer zone which prevents small uncontrolled technical factors from causing major
317
discrepancies in interpretation. A report of “Resistant” indicates that the pathogen
318
is not likely to be inhibited if the antimicrobial compound in the blood reaches the
319
concentrations usually achievable; other therapy should be selected.
320
321
Standardized susceptibility test procedures require the use of laboratory control
322
microorganisms to control the technical aspects of the laboratory procedures.
323
Standard ciprofloxacin powder should provide the following MIC values:
324
325
Organism
MIC (µg/mL)
326
327
E. faecalis
ATCC 29212
0.25-2.0
328
E. coli
ATCC 25922
0.004-0.015
329
H. influenzae
a
ATCC 49247
0.004-0.03
330
N. gonorrhoeae
b
ATCC 49226
0.001-0.008
331
P. aeruginosa
ATCC 27853
0.25-1.0
332
S. aureus
ATCC 29213
0.12-0.5
333
334
a This quality control range is applicable to only H. influenzae ATCC 49247 tested
335
by a broth microdilution procedure using Haemophilus Test Medium (HTM)¹.
336
337
b This quality control range is applicable to only N. gonorrhoeae ATCC 49226
338
tested by an agar dilution procedure using GC agar base and 1% defined growth
339
supplement.
340
341
Diffusion Techniques: Quantitative methods that require measurement of zone
342
diameters also provide reproducible estimates of the susceptibility of bacteria to
343
antimicrobial compounds. One such standardized procedure2 requires the use
344
of standardized inoculum concentrations. This procedure uses paper disks
345
impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
346
ciprofloxacin.
347
348
Reports from the laboratory providing results of the standard single-disk
349
susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to
350
the following criteria:
351
352
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
For testing aerobic microorganisms other than Haemophilus influenzae,
353
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
354
355
Zone Diameter (mm)
Interpretation
356
>21
Susceptible (S)
357
16-20
Intermediate (I)
358
<15
Resistant (R)
359
360
a These zone diameter standards are applicable only to tests performed for
361
streptococci using Mueller-Hinton agar supplemented with 5% sheep blood
362
incubated in 5% CO2.
363
364
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
365
366
Zone Diameter(mm)
Interpretation
367
21
Susceptible (S)
368
369
b This zone diameter standard is applicable only to tests with Haemophilus
370
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium
371
(HTM)
2.
372
373
The current absence of data on resistant strains precludes defining any results other
374
than “Susceptible”. Strains yielding zone diameter results suggestive of a
375
“nonsusceptible” category should be submitted to a reference laboratory for further
376
testing.
377
378
For testing Neisseria gonorrhoeae
c:
379
380
Zone Diameter (mm)
Interpretation
381
>36
Susceptible (S)
382
383
c This zone diameter standard is applicable only to disk diffusion tests with GC agar
384
base and 1% defined growth supplement.
385
386
The current absence of data on resistant strains precludes defining any results other
387
than “Susceptible”. Strains yielding zone diameter results suggestive of a
388
“nonsusceptible” category should be submitted to a reference laboratory for further
389
testing.
390
391
Interpretation should be as stated above for results using dilution techniques.
392
Interpretation involves correlation of the diameter obtained in the disk test with the
393
MIC for ciprofloxacin.
394
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
395
As with standardized dilution techniques, diffusion methods require the use of
396
laboratory control microorganisms that are used to control the technical aspects of
397
the laboratory procedures. For the diffusion technique, the 5-µg ciprofloxacin disk
398
should provide the following zone diameters in these laboratory test quality control
399
strains:
400
401
Organism
Zone Diameter (mm)
402
E. coli
ATCC 25922
30-40
403
H. influenzae
a
ATCC 49247
34-42
404
N. gonorrhoeae
b
ATCC 49226
48-58
405
P. aeruginosa
ATCC 27853
25-33
406
S. aureus
ATCC 25923
22-30
407
408
aThese quality control limits are applicable to only H. influenzae ATCC 49247
409
testing using Haemophilus Test Medium (HTM)².
410
411
b These quality control limits are applicable only to tests conducted with N.
412
gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and
413
1% defined growth supplement.
414
415
INDICATIONS AND USAGE
416
CIPRO® is indicated for the treatment of infections caused by susceptible strains of
417
the designated microorganisms in the conditions listed below. Please see
418
DOSAGE AND ADMINISTRATION for specific recommendations.
419
420
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae,
421
or Moraxella catarrhalis.
422
423
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella
424
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas
425
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or
426
Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute
427
exacerbations of chronic bronchitis.
428
429
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
430
the treatment of presumed or confirmed pneumonia secondary to Streptococcus
431
pneumoniae.
432
433
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
434
Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
435
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
436
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus
437
saprophyticus, or Enterococcus faecalis.
438
439
Acute Uncomplicated Cystitis in females caused by Escherichia coli or
440
Staphylococcus saprophyticus. (See DOSAGE AND ADMINSTRATION.)
441
442
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
443
444
Complicated Intra-Abdominal Infections (used in combination with
445
metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
446
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. (See DOSAGE AND
447
ADMINSTRATION.)
448
449
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella
450
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
451
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas
452
aeruginosa, Staphylococcus aureus (methicillin susceptible), Staphylococcus
453
epidermidis, or Streptococcus pyogenes.
454
455
Bone and Joint Infections caused by Enterobacter cloacae, Serratia
456
marcescens, or Pseudomonas aeruginosa.
457
458
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains),
459
Campylobacter jejuni, Shigella boydii*, Shigella dysenteriae, Shigella Flexneri or
460
Shigella sonnei
* when antibacterial therapy is indicated.
461
462
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
463
464
NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier
465
state has not been demonstrated.
466
467
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
468
469
Inhalational anthrax (post-exposure): To reduce the incidence or progression of
470
disease following exposure to aerosolized Bacillus anthracis.
471
472
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate
473
endpoint reasonably likely to predict clinical benefit and provide the basis for this
474
indication.
4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
475
INFORMATION).
476
477
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
*Although treatment of infections due to this organism in this organ system
478
demonstrated a clinically significant outcome, efficacy was studied in fewer than 10
479
patients.
480
481
If anaerobic organisms are suspected of contributing to the infection, appropriate
482
therapy should be administered.
483
484
Appropriate culture and susceptibility tests should be performed before treatment in
485
order to isolate and identify organisms causing infection and to determine their
486
susceptibility to ciprofloxacin. Therapy with CIPRO® may be initiated before results
487
of these tests are known; once results become available appropriate therapy should
488
be continued. As with other drugs, some strains of Pseudomonas aeruginosa may
489
develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and
490
susceptibility testing performed periodically during therapy will provide information
491
not only on the therapeutic effect of the antimicrobial agent but also on the possible
492
emergence of bacterial resistance.
493
494
CONTRAINDICATIONS
495
CIPRO® (ciprofloxacin hydrochloride) is contraindicated in persons with a history of
496
hypersensitivity to ciprofloxacin or any member of the quinolone class of
497
antimicrobial agents.
498
499
WARNINGS
500
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC
501
PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), -
502
EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE),
503
PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN
504
ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and
505
Nursing Mothers subsections.) The oral administration of ciprofloxacin caused
506
lameness in immature dogs. Histopathological examination of the weight-bearing
507
joints of these dogs revealed permanent lesions of the cartilage. Related
508
quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
509
and other signs of arthropathy in immature animals of various species. (See
510
ANIMAL PHARMACOLOGY.)
511
512
Convulsions, increased intracranial pressure, and toxic psychosis have been
513
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may
514
also cause central nervous system (CNS) events including: dizziness, confusion,
515
tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
516
reactions may occur following the first dose. If these reactions occur in patients
517
receiving ciprofloxacin, the drug should be discontinued and appropriate measures
518
instituted. As with all quinolones, ciprofloxacin should be used with caution in
519
patients with known or suspected CNS disorders that may predispose to seizures
520
or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in
521
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
the presence of other risk factors that may predispose to seizures or lower the
522
seizure threshold (e.g. certain drug therapy, renal dysfunction). (See
523
PRECAUTIONS: General, Information for Patients, Drug Interactions and
524
ADVERSE REACTIONS.)
525
526
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
527
RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND
528
THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status
529
epilepticus, and respiratory failure. Although similar serious adverse effects have
530
been reported in patients receiving theophylline alone, the possibility that these
531
reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant
532
use cannot be avoided, serum levels of theophylline should be monitored and
533
dosage adjustments made as appropriate.
534
535
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
536
following the first dose, have been reported in patients receiving quinolone therapy.
537
Some reactions were accompanied by cardiovascular collapse, loss of
538
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.
539
Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic
540
reactions require immediate emergency treatment with epinephrine. Oxygen,
541
intravenous steroids, and airway management, including intubation, should be
542
administered as indicated.
543
544
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia,
545
jaundice, and hepatic necrosis with fatal outcome have also been rarely reported in
546
patients receiving ciprofloxacin along with other drugs. The possibility that these
547
reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be
548
discontinued at the first appearance of a skin rash or any other sign of
549
hypersensitivity.
550
551
Pseudomembranous colitis has been reported with nearly all antibacterial
552
agents, including ciprofloxacin, and may range in severity from mild to life-
553
threatening. Therefore, it is important to consider this diagnosis in patients
554
who present with diarrhea subsequent to the administration of antibacterial
555
agents.
556
557
Treatment with antibacterial agents alters the normal flora of the colon and may
558
permit overgrowth of clostridia. Studies indicate that a toxin produced by
559
Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
560
561
After the diagnosis of pseudomembranous colitis has been established, therapeutic
562
measures should be initiated. Mild cases of pseudomembranous colitis usually
563
respond to drug discontinuation alone. In moderate to severe cases, consideration
564
should be given to management with fluids and electrolytes, protein
565
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
supplementation, and treatment with an antibacterial drug clinically effective against
566
C. difficile colitis.
567
568
Achilles and other tendon ruptures that required surgical repair or resulted in
569
prolonged disability have been reported with ciprofloxacin and other quinolones.
570
Ciprofloxacin should be discontinued if the patient experiences pain, inflammation,
571
or rupture of a tendon.
572
573
Ciprofloxacin has not been shown to be effective in the treatment of syphilis.
574
Antimicrobial agents used in high dose for short periods of time to treat gonorrhea
575
may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea
576
should have a serologic test for syphilis at the time of diagnosis. Patients treated
577
with ciprofloxacin should have a follow-up serologic test for syphilis after three
578
months.
579
580
PRECAUTIONS
581
General: Crystals of ciprofloxacin have been observed rarely in the urine of human
582
subjects but more frequently in the urine of laboratory animals, which is usually
583
alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin
584
has been reported only rarely in humans because human urine is usually acidic.
585
Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
586
should be well hydrated to prevent the formation of highly concentrated urine.
587
588
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
589
events, including: nervousness, agitation, insomnia, anxiety, nightmares or
590
paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)
591
592
Alteration of the dosage regimen is necessary for patients with impairment of renal
593
function. (See DOSAGE AND ADMINISTRATION.)
594
595
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction
596
has been observed in patients who are exposed to direct sunlight while receiving
597
some members of the quinolone class of drugs. Excessive sunlight should be
598
avoided. Therapy should be discontinued if phototoxicity occurs.
599
600
As with any potent drug, periodic assessment of organ system functions, including
601
renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
602
603
Information for Patients:
604
Patients should be advised:
605
♦ that ciprofloxacin may be taken with or without meals and to drink fluids liberally.
606
As with other quinolones, concurrent administration of ciprofloxacin with
607
magnesium/aluminum antacids, or sucralfate, Videx (didanosine)
608
chewable/buffered tablets or pediatric powder, or with other products containing
609
calcium, iron or zinc should be avoided. These products may be taken two
610
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
hours after or six hours before ciprofloxacin. Ciprofloxacin should not be taken
611
concurrently with milk or yogurt alone, since absorption of ciprofloxacin may be
612
significantly reduced. Dietary calcium as part of a meal, however, does not
613
significantly affect ciprofloxacin absorption
614
615
♦ that ciprofloxacin may be associated with hypersensitivity reactions, even
616
following a single dose, and to discontinue the drug at the first sign of a skin rash
617
or other allergic reaction.
618
619
♦ to avoid excessive sunlight or artificial ultraviolet light while receiving
620
ciprofloxacin and to discontinue therapy if phototoxicity occurs.
621
622
♦ to discontinue treatment; rest and refrain from exercise; and inform their
623
physician if they experience pain, inflammation, or rupture of a tendon.
624
625
♦ that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients
626
should know how they react to this drug before they operate an automobile or
627
machinery or engage in activities requiring mental alertness or coordination.
628
629
♦ that ciprofloxacin may increase the effects of theophylline and caffeine. There is
630
a possibility of caffeine accumulation when products containing caffeine are
631
consumed while taking quinolones.
632
633
♦ that convulsions have been reported in patients receiving quinolones, including
634
ciprofloxacin, and to notify their physician before taking this drug if there is a
635
history of this condition.
636
637
Drug Interactions: As with some other quinolones, concurrent administration of
638
ciprofloxacin with theophylline may lead to elevated serum concentrations of
639
theophylline and prolongation of its elimination half-life. This may result in increased
640
risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
641
use cannot be avoided, serum levels of theophylline should be monitored and
642
dosage adjustments made as appropriate.
643
644
Some quinolones, including ciprofloxacin, have also been shown to interfere with the
645
metabolism of caffeine. This may lead to reduced clearance of caffeine and a
646
prolongation of its serum half-life.
647
648
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent
649
cation-containing products such as magnesium/aluminum antacids, sucralfate,
650
Videx (didanosine) chewable/buffered tablets or pediatric powder, or products
651
containing calcium, iron, or zinc may substantially decrease its absorption, resulting
652
in serum and urine levels considerably lower than desired. (See DOSAGE AND
653
ADMINSTRATION for concurrent administration of these agents with ciprofloxacin.)
654
655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Histamine H2-receptor antagonists appear to have no significant effect on the
656
bioavailability of ciprofloxacin.
657
658
Altered serum levels of phenytoin (increased and decreased) have been reported in
659
patients receiving concomitant ciprofloxacin.
660
661
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has,
662
on rare occasions, resulted in severe hypoglycemia.
663
664
Some quinolones, including ciprofloxacin, have been associated with transient
665
elevations in serum creatinine in patients receiving cyclosporine concomitantly.
666
667
Quinolones have been reported to enhance the effects of the oral anticoagulant
668
warfarin or its derivatives. When these products are administered concomitantly,
669
prothrombin time or other suitable coagulation tests should be closely monitored.
670
671
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces
672
an increase in the level of ciprofloxacin in the serum. This should be considered
673
if patients are receiving both drugs concomitantly.
674
675
As with other broad spectrum antimicrobial agents, prolonged use of ciprofloxacin
676
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the
677
patient’s condition and microbial susceptibility testing is essential. If superinfection
678
occurs during therapy, appropriate measures should be taken.
679
680
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro
681
mutagenicity tests have been conducted with ciprofloxacin, and the test results are
682
listed below:
683
684
Salmonella/Microsome Test (Negative)
685
E. coli DNA Repair Assay (Negative)
686
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
687
Chinese Hamster V79 Cell HGPRT Test (Negative)
688
Syrian Hamster Embryo Cell Transformation Assay (Negative)
689
Saccharomyces cerevisiae Point Mutation Assay (Negative)
690
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion
691
Assay (Negative)
692
Rat Hepatocyte DNA Repair Assay (Positive)
693
694
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems
695
gave negative results:
696
697
Rat Hepatocyte DNA Repair Assay
698
Micronucleus Test (Mice)
699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Dominant Lethal Test (Mice)
700
701
Long-term carcinogenicity studies in mice and rats have been completed. After
702
daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up
703
to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or
704
tumorigenic effects in these species.
705
706
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not
707
reduce the time to appearance of UV-induced skin tumors as compared to vehicle
708
control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times
709
every two weeks for up to 78 weeks while concurrently being administered
710
ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
711
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal
712
to maximum recommended human dose based upon mg/m
2), as opposed to 34
713
weeks when animals were treated with both UVA and vehicle. The times to
714
development of skin tumors ranged from 16-32 weeks in mice treated concomitantly
715
with UVA and other quinolones.
3
716
717
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic
718
tumors. There are no data from similar models using pigmented mice and/or fully
719
haired mice. The clinical significance of these findings to humans is unknown.
720
721
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (0.8
722
times the highest recommended human dose of 1200 mg based upon body surface
723
area) revealed no evidence of impairment.
724
725
Pregnancy: Teratogenic Effects. Pregnancy Category C: Reproduction
726
studies have been performed in rats and mice using oral doses up to 100 mg/kg
727
(0.6 and 0.3 times the maximum daily human dose based upon body surface area,
728
respectively) and have revealed no evidence of harm to the fetus due to
729
ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced
730
gastrointestinal disturbances resulting in maternal weight loss and an increased
731
incidence of abortion, but no teratogenicity was observed at either dose. After
732
intravenous administration of doses up to 20 mg/kg, no maternal toxicity was
733
produced in the rabbit, and no embryotoxicity or teratogenicity was observed.
734
There are, however, no adequate and well-controlled studies in pregnant women.
735
Ciprofloxacin should be used during pregnancy only if the potential benefit justifies
736
the potential risk to the fetus. (See WARNINGS.)
737
738
Nursing Mothers: Ciprofloxacin is excreted in human milk. Because of the
739
potential for serious adverse reactions in infants nursing from mothers taking
740
ciprofloxacin, a decision should be made whether to discontinue nursing or to
741
discontinue the drug, taking into account the importance of the drug to the mother.
742
743
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Pediatric Use: Safety and effectiveness in pediatric patients and adolescents less
744
than 18 years of age have not been established, except for use in inhalational
745
anthrax (post-exposure). Ciprofloxacin causes arthropathy in juvenile animals. (See
746
WARNINGS.)
747
748
For the indication of inhalational anthrax (post-exposure), the risk-benefit
749
assessment indicates that administration of ciprofloxacin to pediatric patients is
750
appropriate. For information regarding pediatric dosing in inhalational anthrax
751
(post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
752
ANTHRAX – ADDITIONAL INFORMATION.
753
754
Short-term safety data from a single trial in pediatric cystic fibrosis patients are
755
available. In a randomized, double-blind clinical trial for the treatment of acute
756
pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients
757
received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by
758
ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
759
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and
760
tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 - 21 days. Patients less than 5
761
years of age were not studied. Safety monitoring in the study included periodic
762
range of motion examinations and gait assessments by treatment-blinded
763
examiners. Patients were followed for an average of 23 days after completing
764
treatment (range 0-93 days). This study was not designed to determine long term
765
effects and the safety of repeated exposure to ciprofloxacin.
766
767
In the study, injection site reactions were more common in the ciprofloxacin group
768
(24%) than in the comparison group (8%). Other adverse events were similar in
769
nature and frequency between treatment arms. Musculoskeletal adverse events
770
were reported in 22% of the patients in the ciprofloxacin group and 21% in the
771
comparison group. Decreased range of motion was reported in 12% of the
772
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia
773
was reported in 10% of the patients in the ciprofloxacin group and 11% in the
774
comparison group. One of sixty-seven patients developed arthritis of the knee nine
775
days after a ten day course of treatment with ciprofloxacin. Clinical symptoms
776
resolved, but an MRI showed knee effusion without other abnormalities eight months
777
after treatment. However, the relationship of this event to the patient’s course of
778
ciprofloxacin can not be definitively determined, particularly since patients with
779
cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease
780
process.
781
782
Geriatric Use : In a retrospective analysis of 23 multiple-dose controlled clinical
783
trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25%
784
of patients were greater than or equal to 65 years of age and 10% were greater
785
than or equal to 75 years of age. No overall differences in safety or effectiveness
786
were observed between these subjects and younger subjects, and other reported
787
clinical experience has not identified differences in responses between the elderly
788
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
and younger patients, but greater sensitivity of some older individuals on any drug
789
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by
790
the kidney, and the risk of adverse reactions may be greater in patients with
791
impaired renal function. No alteration of dosage is necessary for patients greater
792
than 65 years of age with normal renal function. However, since some older
793
individuals experience reduced renal function by virtue of their advanced age, care
794
should be taken in dose selection for elderly patients, and renal function monitoring
795
may be useful in these patients. (See CLINICAL PHARMACOLOGY and
796
DOSAGE AND ADMINISTRATION.)
797
798
ADVERSE REACTIONS
799
During clinical investigation with the tablet, 2,799 patients received 2,868 courses
800
of the drug. Adverse events that were considered likely to be drug related occurred
801
in 7.3% of patients treated, possibly related in 9.2% (total of 16.5% thought to be
802
possibly or probably related to drug therapy), and remotely related in 3.0%.
803
Ciprofloxacin was discontinued because of an adverse event in 3.5% of patients
804
treated, primarily involving the gastrointestinal system (1.5%), skin (0.6%), and
805
central nervous system (0.4%).
806
807
The most frequently reported events, drug related or not, were nausea (5.2%),
808
diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache
809
(1.2%), restlessness (1.1%), and rash (1.1%).
810
811
Additional events that occurred in less than 1% of ciprofloxacin patients are listed
812
below.
813
814
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope,
815
hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest,
816
cerebral thrombosis
817
CENTRAL NERVOUS SYSTEM: dizziness, lightheadedness, insomnia,
818
nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive
819
seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia,
820
depersonalization, depression, paresthesia (See above.) (See
821
PRECAUTIONS.)
822
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia,
823
intestinal perforation, gastrointestinal bleeding (See above.) Cholestatic
824
jaundice has been reported.
825
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or
826
chest pain, flare up of gout
827
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria,
828
urinary retention, urethral bleeding, vaginitis, acidosis
829
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough,
830
hemoptysis, bronchospasm, pulmonary embolism
831
SKIN/HYPERSENSITIVITY: pruritus, urticaria, photosensitivity, flushing, fever,
832
chills, angioedema, edema of the face, neck, lips, conjunctivae or hands,
833
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
cutaneous candidiasis, hyperpigmentation, erythema nodosum (See above.)
834
Allergic reactions ranging from urticaria to anaphylactic reactions have been
835
reported. (See WARNINGS.)
836
SPECIAL SENSES: blurred vision, disturbed vision (change in color
837
perception, overbrightness of lights), decreased visual acuity, diplopia, eye
838
pain, tinnitus, hearing loss, bad taste
839
840
Most of the adverse events reported were described as only mild or moderate in
841
severity, abated soon after the drug was discontinued, and required no treatment.
842
843
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged
844
by investigators to be related to elevated serum levels of theophylline possibly as a
845
result of drug interaction with ciprofloxacin.
846
847
In domestic clinical trials involving 214 patients receiving a single 250-mg oral dose,
848
approximately 5% of patients reported adverse experiences without reference to
849
drug relationship. The most common adverse experiences were vaginitis (2%),
850
headache (1%), and vaginal pruritus (1%). Additional reactions, occurring in 0.3%-
851
1% of patients, were abdominal discomfort, lymphadenopathy, foot pain, dizziness,
852
and breast pain. Less than 20% of these patients had laboratory values obtained,
853
and these results were generally consistent with the pattern noted for multi-dose
854
therapy.
855
856
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets
857
(500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500
858
mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a
859
CNS adverse event profile comparable to the control drugs.
860
861
Post-Marketing Adverse Events: Additional adverse events, regardless of
862
relationship to drug, reported from worldwide marketing experience with quinolones,
863
including ciprofloxacin, are:
864
BODY AS A WHOLE: change in serum phenytoin
865
CARDIOVASCULAR: postural hypotension, vasculitis
866
CENTRAL NERVOUS SYSTEM: agitation, confusion, delirium, dysphasia,
867
myoclonus, nystagmus, toxic psychosis
868
GASTROINTESTINAL: constipation, dyspepsia, flatulence, hepatic necrosis,
869
jaundice, pancreatitis, pseudomembranous colitis (The onset of
870
pseudomembranous colitis symptoms may occur during or after antimicrobial
871
treatment.)
872
HEMIC/LYMPHATIC: agranulocytosis, hemolytic anemia, methemoglobinemia,
873
prolongation of prothrombin time
874
METABOLIC/NUTRITIONAL: elevation of serum triglycerides, cholesterol,
875
blood glucose, serum potassium
876
MUSCULOSKELETAL: myalgia, possible exacerbation of myasthenia gravis,
877
tendinitis/tendon rupture
878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
RENAL/UROGENITAL: albuminuria, candiduria, renal calculi, vaginal
879
candidiasis
880
SKIN/HYPERSENSITIVITY: anaphylactic reactions, erythema
881
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal
882
necrolysis
883
SPECIAL SENSES: anosmia, taste loss (See PRECAUTIONS.)
884
885
Adverse Laboratory Changes: Changes in laboratory parameters listed as
886
adverse events without regard to drug relationship are listed below:
887
888
Hepatic -
Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%),
889
alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin
890
(0.3%).
891
Hematologic -
Eosinophilia (0.6%), leukopenia (0.4%), decreased blood
892
platelets (0.1%), elevated blood platelets (0.1%),
893
pancytopenia (0.1%).
894
Renal -
Elevations of serum creatinine (1.1%), BUN (0.9%),
895
CRYSTALLURIA, CYLINDRURIA, AND HEMATURIA HAVE
896
BEEN REPORTED.
897
898
Other changes occurring in less than 0.1% of courses were: elevation of serum
899
gammaglutamyl transferase, elevation of serum amylase, reduction in blood
900
glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis,
901
increase in blood monocytes, leukocytosis.
902
903
OVERDOSAGE
904
In the event of acute overdosage, the stomach should be emptied by inducing
905
vomiting or by gastric lavage. The patient should be carefully observed and given
906
supportive treatment. Adequate hydration must be maintained. Only a small
907
amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or
908
peritoneal dialysis.
909
910
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions
911
was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
912
913
Single doses of ciprofloxacin were relatively non-toxic via the oral route of
914
administration in mice, rats, and dogs. No deaths occurred within a 14-day post
915
treatment observation period at the highest oral doses tested; up to 5000 mg/kg in
916
either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed
917
included hypoactivity and cyanosis in both rodent species and severe vomiting in
918
dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500
919
mg/kg. Mortality was delayed in these animals, occurring 10-14 days after dosing.
920
921
DOSAGE AND ADMINSTRATION
922
923
The recommended adult dosage for acute sinusitis is 500-mg every 12 hours.
924
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
925
Lower respiratory tract infections may be treated with 500-mg every 12 hours. For
926
more severe or complicated infections, a dosage of 750-mg may be given every 12
927
hours.
928
929
Severe/complicated urinary tract infections or urinary tract infections caused by
930
organisms not highly susceptible to ciprofloxacin may be treated with 500-mg every
931
12 hours. For other mild/moderate urinary infections, the usual adult dosage is 250-
932
mg every 12 hours.
933
934
In acute uncomplicated cystitis in females, the usual dosage is 100-mg or 250-mg
935
every 12 hours. For acute uncomplicated cystitis in females, 3 days of treatment is
936
recommended while 7 to 14 days is suggested for other mild/moderate, severe or
937
complicated urinary tract infections.
938
939
The recommended adult dosage for chronic bacterial prostatitis is 500-mg every 12
940
hours.
941
942
The recommended adult dosage for oral sequential therapy of complicated intra-
943
abdominal infections is 500-mg every 12 hours. (To provide appropriate anaerobic
944
activity, metronidazole should be given according to product labeling.) (See
945
CIPRO® I.V. package insert.)
946
947
Skin and skin structure infections and bone and joint infections may be treated with
948
500-mg every 12 hours. For more severe or complicated infections, a dosage of
949
750-mg may be given every 12 hours.
950
951
The recommended adult dosage for infectious diarrhea or typhoid fever is 500-mg
952
every 12 hours. For the treatment of uncomplicated urethral and cervical
953
gonococcal infections, a single 250-mg dose is recommended.
954
955
See Instructions To The Pharmacist for Use/Handling of CIPRO® Oral
956
Suspension.
957
958
DOSAGE GUIDELINES
Infection Type or Severity Unit Dose Frequency Usual
Durations†
Acute Sinusitis
Mild/Moderate
500-mg
q 12 h
10 days
Lower Respiratory
Tract
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
7 to 14 days
7 to 14 days
Urinary Tract
Acute Uncomplicated
Mild/Moderate
Severe/Complicated
100-mg or 250-mg
250-mg
500-mg
q 12 h
q 12 h
q 12 h
3 Days
7 to 14 Days
7 to 14 Days
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Chronic Bacterial
Prostatitis
Mild/Moderate
500-mg
q 12 h
28 Days
Intra-Abdominal*
Complicated
500-mg
q 12 h
7 to 14 Days
Skin and Skin Structure
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
7 to 14 Days
7 to 14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
500-mg
750-mg
q 12 h
q 12 h
> 4 to 6 weeks
> 4 to 6 weeks
Infectious Diarrhea
Mild/Moderate/Severe
500-mg
q 12 h
5 to 7 Days
Typhoid Fever
Mild/Moderate
500-mg
q 12 h
10 Days
Urethral and Cervical
Gonococcal Infections
Uncomplicated
250-mg
single dose
single dose
Inhalational anthrax
(post-exposure)**
Adult
Pediatric
500-mg
15 mg/kg per
dose, not to
exceed 500-mg
per dose
q 12 h
q 12 h
60 Days
60 Days
* used in conjunction with metronidazole
959
† Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of
960
infection have disappeared, except for inhalational anthrax (post-exposure).
961
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
962
This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in
963
humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum
964
concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
965
INFORMATION.
966
967
One teaspoonful (5 mL) of 5% ciprofloxacin oral suspension = 250-mg of
968
ciprofloxacin.
969
One teaspoonful (5 mL) of 10% ciprofloxacin oral suspension = 500-mg of
970
ciprofloxacin.
971
See Instructions for USE/HANDLING.
972
973
Volume (mL) of Oral Suspension
974
Dosage
5%
10%
975
250-mg
5 mL
2.5 mL
976
500-mg
10 mL
5 mL
977
750-mg
15 mL
7.5 mL
978
979
CIPRO (ciprofloxacin) 5% and 10% Oral Suspension should not be
980
administered through feeding tubes due to its physical characteristics.
981
982
Complicated Intra-Abdominal Infections: Sequential therapy [parenteral to oral -
983
400-mg CIPRO® IV q 12 h (plus IV metronidazole) è 500-mg CIPRO® Tablets q
984
12 h (plus oral metronidazole)] can be instituted at the discretion of the physician.
985
986
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
The determination of dosage for any particular patient must take into consideration
987
the severity and nature of the infection, the susceptibility of the causative organism,
988
the integrity of the patient’s host-defense mechanisms, and the status of renal
989
function and hepatic function.
990
991
The duration of treatment depends upon the severity of infection. Generally
992
ciprofloxacin should be continued for at least 2 days after the signs and symptoms
993
of infection have disappeared. The usual duration is 7 to 14 days; however, for
994
severe and complicated infections more prolonged therapy may be required. Bone
995
and joint infections may require treatment for 4 to 6 weeks or longer. Chronic
996
Bacterial Prostatitis should be treated for 28 days. Infectious diarrhea may be
997
treated for 5-7 days. Typhoid fever should be treated for 10 days.
998
999
Ciprofloxacin should be administered at least 2 hours before or 6 hours after
1000
magnesium/aluminum antacids, or sucralfate, Videx (Didanoside) chewable /
1001
buffereed tablets or pediatric powder for oral solution, or other products containg
1002
calcium, iron or zinc.
1003
1004
Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
1005
however, the drug is also metabolized and partially cleared through the biliary
1006
system of the liver and through the intestine. These alternate pathways of drug
1007
elimination appear to compensate for the reduced renal excretion in patients with
1008
renal impairment. Nonetheless, some modification of dosage is recommended,
1009
particularly for patients with severe renal dysfunction. The following table provides
1010
dosage guidelines for use in patients with renal impairment; however, monitoring of
1011
serum drug levels provides the most reliable basis for dosage adjustment:
1012
1013
RECOMMENDED STARTING AND MAINTENANCE DOSES
1014
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
1015
1016
Creatinine Clearance (mL/min)
Dose
1017
>50
See Usual Dosage.
1018
30 - 50
250-500 mg q 12 h
1019
5 - 29
250-500 mg q 18 h
1020
Patients on hemodialysis
250-500 mg q 24 h (after dialysis)
1021
or Peritoneal dialysis)
1022
1023
When only the serum creatinine concentration is known, the following formula may
1024
be used to estimate creatinine clearance.
1025
1026
Men: Creatinine clearance (mL/min) = Weight (kg) x (140-age)
1027
72 x serum creatinine (mg/dL)
1028
1029
Women: 0.85 x the value calculated for men.
1030
The serum creatinine should represent a steady state of renal function.
1031
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
1032
In patients with severe infections and severe renal impairment, a unit dose of 750-
1033
mg may be administered at the intervals noted above; however, patients should be
1034
carefully monitored and the serum ciprofloxacin concentration should be measured
1035
periodically. Peak concentrations (1-2 hours after dosing) should generally range
1036
from 2 to 4 µg/mL.
1037
1038
For patients with changing renal function or for patients with renal impairment and
1039
hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will
1040
provide additional guidance for adjusting dosage.
1041
1042
HOW SUPPLIED
1043
CIPRO® (ciprofloxacin hydrochloride) Tablets are available as round, slightly
1044
yellowish film-coated tablets containing 100-mg or 250-mg ciprofloxacin. The 100-
1045
mg tablet is coded with the word “CIPRO” on one side and “100” on the reverse
1046
side. The 250-mg tablet is coded with the word “CIPRO” on one side and “250” on
1047
the reverse side. CIPRO® is also available as capsule shaped, slightly yellowish
1048
film-coated tablets containing 500-mg or 750-mg ciprofloxacin. The 500-mg tablet
1049
is coded with the word “CIPRO” on one side and “500” on the reverse side. The
1050
750-mg tablet is coded with the word “CIPRO” on one side and “750” on the reverse
1051
side. CIPRO® 250-mg, 500-mg, and 750-mg are available in bottles of 50, 100,
1052
and Unit Dose packages of 100. The 100-mg strength is available only as CIPRO®
1053
Cystitis pack containing 6 tablets for use only in female patients with acute
1054
uncomplicated cystitis.
1055
1056
Strength
NDC Code
Tablet Identification
1057
1058
Bottles of 50:
750-mg
NDC 0026-8514-50 CIPRO 750
1059
Bottles of 100:
250-mg
NDC 0026-8512-51 CIPRO 250
1060
500-mg
NDC 0026-8513-51 CIPRO 500
1061
1062
Unit Dose
1063
Package of 100:
250-mg
NDC 0026-8512-48 CIPRO 250
1064
500-mg
NDC 0026-8513-48 CIPRO 500
1065
750-mg
NDC 0026-8514-48 CIPRO 750
1066
1067
Cystitis
1068
Package of 6:
100-mg
NDC 0026-8511-06
CIPRO 100
1069
1070
Store below 30°° C (86°° F).
1071
1072
CIPRO ® Oral Suspension is supplied in 5% (5g ciprofloxacin in 100 mL) and 10%
1073
(10g ciprofloxacin in 100 mL) strengths. The drug product is composed of two
1074
components (microcapsules and diluent) which are mixed prior to dispensing. See
1075
Instructions To The Pharmacist For Use/Handling.
1076
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
1077
1078
Total
Ciprofloxacin
Ciprofloxacin
1079
volume after
contents after
contents per
1080
reconstitution
reconstitution
bottle
NDC Code
1081
1082
100 mL
250 mg/5 mL
5,000 mg
0026-8551-36
1083
100 mL
500 mg/5 mL
10,000 mg
0026-8553-36
1084
1085
Microcapsules and diluent should be stored below 25°° C (77°° F) and
1086
protected from freezing.
1087
Reconstituted product may be stored below 30°° C (86°° F). Protect from
1088
freezing. A teaspoon is provided for the patient.
1089
1090
ANIMAL PHARMACOLOGY
1091
Ciprofloxacin and other quinolones have been shown to cause arthropathy in
1092
immature animals of most species tested. (See WARNINGS.) Damage of weight
1093
bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
1094
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the
1095
knee joint. At 30 mg/kg, the effect on the joint was minimal . In a subsequent study
1096
in beagles, removal of weight bearing from the joint reduced the lesions but did not
1097
totally prevent them.
1098
1099
Crystalluria, sometimes associated with secondary nephropathy, occurs in
1100
laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced
1101
solubility of ciprofloxacin under alkaline conditions, which predominate in the urine
1102
of test animals; in man, crystalluria is rare since human urine is typically acidic. In
1103
rhesus monkeys, crystalluria without nephropathy has been noted after single oral
1104
doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no
1105
nephropathological changes were noted; however, nephropathy was observed after
1106
dosing at 20 mg/kg/day for the same duration.
1107
1108
In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid IV injection (15 sec.) produces
1109
pronounced hypotensive effects. These effects are considered to be related to
1110
histamine release, since they are partially antagonized by pyrilamine, an
1111
antihistamine. In rhesus monkeys, rapid IV injection also produces hypotension but
1112
the effect in this species is inconsistent and less pronounced.
1113
1114
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as
1115
phenylbutazone and indomethacin with quinolones has been reported to enhance
1116
the CNS stimulatory effect of quinolones.
1117
1118
Ocular toxicity seen with some related drugs has not been observed in
1119
ciprofloxacin-treated animals.
1120
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
1121
CLINICAL STUDIES
1122
Acute Sinusitis Studies
1123
Ciprofloxacin tablets (500-mg BID) were evaluated for the treatment of acute
1124
sinusitis in two randomized, double-blind, controlled clinical trials conducted in the
1125
United States. Study 1 compared ciprofloxacin with cefuroxime axetil (250-mg BID)
1126
and enrolled 501 patients (400 of whom were valid for the primary efficacy analysis).
1127
Study 2 compared ciprofloxacin with clarithromycin (500-mg BID) and enrolled 560
1128
patients (418 of whom were valid for the primary efficacy analysis). The primary test
1129
of cure endpoint was a follow-up visit performed approximately 30 days after the
1130
completion of treatment with study medication. Clinical response data from these
1131
studies are summarized below:
1132
1133
Drug Regimen
Clinical Response Resolution
1134
at 30 Day Follow-up n(%)
1135
STUDY 1
1136
CIPRO 500-mg
152/197 (77)
1137
BID x 10 days
1138
1139
Cefuroxime Axetil 250-mg
145/203 (71)
1140
BID x 10 days
1141
STUDY 2
1142
CIPRO 500-mg
168/212 (79)
1143
BID x 10 days
1144
1145
Clarithromycin 500-mg
169/206 (82)
1146
BID x 14 days
1147
1148
In ciprofloxacin-treated patients enrolled in controlled and uncontrolled acute
1149
sinusitis studies, all of which included antral puncture, bacteriological
1150
eradication/presumed eradication was documented at the 30 day follow-up visit in
1151
44 of 50 (88%) H. influenzae, 17 of 21 (80.9%) M. catarrhalis, and 42 of 51
1152
(82.3%) S. pneumoniae. Patients infected with S. pneumoniae strains whose
1153
baseline susceptibilities were intermediate or resistant to ciprofloxacin had a lower
1154
success rate than patients infected with susceptible strains.
1155
1156
Uncomplicated Cystitis Studies
1157
Efficacy: Two U.S. double-blind, controlled clinical studies of acute uncomplicated
1158
cystitis in women compared ciprofloxacin 100-mg BID for 3 days to ciprofloxacin
1159
250-mg BID for 7 days or control drug. In these two studies, using strict evaluability
1160
criteria and microbiologic and clinical response criteria at the 5-9 day post-therapy
1161
follow-up, the following clinical resolution and bacterial eradication rates were
1162
obtained:
1163
1164
Clinical Response
Bacteriological Response By
1165
Organism (Eradication Rate)
1166
1167
Drug Regimen
Resolution n(%)
E. coli n(%)
S. saprophyticus n(%)
1168
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
1169
STUDY 1
1170
CIPRO 100-mg
1171
BID x 3 days
82/94 (87)
64/70 (91)
8/8 (100)
1172
1173
CIPRO 250-mg
1174
BID x 7 days
81/86 (94)
67/69 (97)
4/4 (100)
1175
STUDY 2
1176
CIPRO 100-mg
1177
BID x 3 days
134/141 (95)
117/123 (95)
8/8 (100)
1178
1179
Control
128/133 (96)
103/105 (98)
10/10 (100)
1180
(3 days)
1181
1182
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
1183
1184
The mean serum concentrations of ciprofloxacin associated with a statistically
1185
significant improvement in survival in the rhesus monkey model of inhalational
1186
anthrax are reached or exceeded in adult and pediatric patients receiving oral and
1187
intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin
1188
pharmacokinetics have been evaluated in various human populations. The mean
1189
peak serum concentration achieved at steady state in human adults receiving 500
1190
mg orally every 12 hours is 2.97 µg/ml, and 4.56 µg/ml following 400 mg
1191
intravenously every 12 hours. The mean trough serum concentration at steady state
1192
for both of these regimens is 0.2 µg/ml. In a study of 10 pediatric patients between 6
1193
and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL
1194
and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute
1195
intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
1196
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a
1197
mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety
1198
data, including effects on cartilage, following the administration of ciprofloxacin to
1199
pediatric patients are limited. (For additional information, see PRECAUTIONS,
1200
Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
1201
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
1202
for this indication.
4
1203
1204
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
1205
dose of 11 LD50 (~5.5 x 105) spores (range 5-30 LD50) of B. anthracis was
1206
conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the
1207
anthrax strain used in this study was 0.08 µg/ml. In the animals studied, mean serum
1208
concentrations of ciprofloxacin achieved at expected Tmax
1209
(1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69
1210
µg/ml. Mean steady state trough concentrations at 12 hours post-dose ranged from
1211
0.12 to 0.19 µg/ml
5. Mortality due to anthrax for animals that received a 30-day
1212
regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly
1213
lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
1214
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug
1215
administration period.
6
1216
1217
Instructions To The Pharmacist For Use/Handling Of CIPRO® Oral
1218
Suspension:
1219
1220
Preparation of the suspension:
1221
1222
1223
[IMAGE]
1. The small bottle contains the microcapsules; the
1224
large bottle contains the diluent.
1225
1226
1227
[IMAGE]
2. Open both bottles. Child-proof cap: Press down
1228
according to instructions on the cap while turning to the
1229
left.
1230
1231
[IMAGE]
3. Pour the microcapsules completely into the large
1232
bottle of diluent. Do not add water to the
1233
suspension.
1234
1235
4. Remove the top layer of the diluent bottle label (to
1236
reveal the CIPRO ® Oral Suspension label).
1237
1238
[IMAGE]
5. Close the large bottle completely according to
1239
the directions on the cap and shake vigorously for
1240
about 15 seconds. The suspension is ready for use.
1241
1242
Instructions To The Patient For Taking CIPRO ® Oral Suspension:
1243
1244
Shake vigorously each time before use for approximately 15 seconds.
1245
1246
Swallow the prescribed amount of suspension. Do not chew the microcapsules.
1247
Reclose the bottle completely after use according to the instructions on the cap.
1248
Shake vigorously each time before use for approximately 15 seconds. The product
1249
can be used for 14 days when stored in a refrigerator or at room temperature
1250
(below 86°F). After treatment has been completed, any remaining suspension
1251
should not be reused.
1252
1253
1254
References: 1. National Committee for Clinical Laboratory Standards, Methods for
1255
Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth
1256
Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS,
1257
Wayne, PA, January 2000.
1258
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
2. National Committee for Clinical Laboratory Standards, Performance Standards
1259
for Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard
1260
NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
1261
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
1262
Product’s Advisory Committee meeting, March 31, 1993, Silver Spring MD. Report
1263
available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901
1264
Chapman Avenue, Room 200, Rockville, MD 20852, USA
1265
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-
1266
Threatening Illnesses)
1267
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
1268
during prolonged therapy in rhesus monkeys J Infect Dis 1992; 166: 1184-7.
1269
6. Friedlander AM, et al. Postexposure prophylaxis against experimental
1270
inhalational anthrax J Infect Dis 1993; 167: 1239-42.
1271
1272
1273
Rx Only
1274
PX###### 8/00 Bay o 9867 5202-2-A-U.S.-10
© 2000 Bayer Corporation XXXX
1275
CIPRO (R) (ciprofloxacin) 5% and 10% Oral Suspension Made in Italy. Printed in
1276
U.S.A.
1277
1278
1279
1280
1281
1282
1283
1284
1285
CIPRO® I.V.
1286
(ciprofloxacin)
1287
For Intravenous Infusion
1288
1289
PZXXXXXX
8/29/00
1290
DESCRIPTION
1291
1292
CIPRO® I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for
1293
intravenous (I.V.) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-
1294
6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical
1295
formula is C17H18FN3O3 and its chemical structure is:
1296
1297
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
N
O
F
N
HN
COOH
Ciprofloxacin
1298
1299
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of
1300
331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in
1301
water and ethanol. Ciprofloxacin differs from other quinolones in that it has a
1302
fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a
1303
cyclopropyl ring at the 1-position. CIPRO® I.V. solutions are available as sterile
1304
1.0% aqueous concentrates, which are intended for dilution prior to administration,
1305
and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
1306
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment.
1307
The pH range for the 1% aqueous concentrates in vials is 3.3 to 3.9. The pH range
1308
for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.
1309
1310
The plastic container is fabricated from a specially formulated polyvinyl chloride.
1311
Solutions in contact with the plastic container can leach out certain of its chemical
1312
components in very small amounts within the expiration period, e.g., di(2-ethylhexyl)
1313
phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has been
1314
confirmed in tests in animals according to USP biological tests for plastic
1315
containers as well as by tissue culture toxicity studies.
1316
1317
CLINICAL PHARMACOLOGY
1318
1319
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to
1320
normal volunteers, the mean maximum serum concentrations achieved were 2.1
1321
and 4.6 µg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2
1322
µg/mL, respectively.
1323
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
1324
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
1325
After 60-minute I.V. Infusions q 12 h.
1326
1327
Time after starting the infusion
1328
1329
Dose
30 min. 1 hr 3 hr 6 hr 8 hr 12 hr
1330
200 mg
1.7
2.1 0.6 0.3 0.2 0.1
1331
400 mg
3.7 4.6 1.3 0.7 0.5 0.2
1332
1333
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400
1334
mg administered intravenously. The serum elimination half-life is approximately 5-6
1335
hours and the total clearance is around 35 L/hr. Comparison of the
1336
pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen
1337
indicates no evidence of drug accumulation.
1338
1339
The absolute bioavailability of oral ciprofloxacin is within a range of 70-80% with no
1340
substantial loss by first pass metabolism. An intravenous infusion of 400 mg
1341
ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an
1342
area under the serum concentration time curve (AUC) equivalent to that produced
1343
by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg
1344
ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an
1345
AUC at steady-state equivalent to that produced by a 750-mg oral dose given every
1346
12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-
1347
mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an
1348
AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
1349
1350
Steady-state Pharmacokinetic Parameter
1351
Following Multiple Oral and I.V. Doses
1352
1353
Parameters 500 mg
400 mg
750 mg
400 mg
1354
q12h, P.O.
12h, I.V. q12h, P.O.
q8h, I.V.
1355
1356
AUC (µglhr/mL) 13.7a
12.7a 31.6b 32.9c
1357
Cmax(µg/mL) 2.97
4.56 3.59
4.07
1358
1359
aAUC 0-12h
bAUC 24h=AUC0-12hx2 cAUC 24h=AUC0-8hx3
1360
1361
After intravenous administration, approximately 50% to 70% of the dose is
1362
excreted in the urine as unchanged drug. Following a 200-mg I.V. dose,
1363
concentrations in the urine usually exceed 200 µg/mL 0-2 hours after dosing and are
1364
generally greater than 15 µg/mL 8-12 hours after dosing. Following a 400- mg I.V.
1365
dose, urine concentrations generally exceed 400 µg/mL 0-2 hours after dosing and
1366
are usually greater that 30 µg/mL 8-12 hours after dosing. The renal clearance is
1367
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by
1368
24 hours after dosing.
1369
1370
The serum concentrations of ciprofloxacin and metronidazole were not altered when
1371
these two drugs were given concomitantly.
1372
1373
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction
1374
in the ciprofloxacin renal clearance and a 50% increase in its concentration in the
1375
systemic circulation. Although bile concentrations of ciprofloxacin are several fold
1376
higher than serum concentrations after intravenous dosing, only a small amount of
1377
the administered dose (<1%) is recovered from the bile as unchanged drug.
1378
Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
1379
dosing.
1380
1381
After I.V. administration, three metabolites of ciprofloxacin have been identified in
1382
human urine which together account for approximately 10% of the intravenous dose.
1383
1384
Pharmacokinetic studies of the oral (single dose) and intravenous (single and
1385
multiple dose) forms of ciprofloxacin indicate that plasma concentrations of
1386
ciprofloxacin are higher in elderly subjects (>65 years) as compared to young
1387
adults. Although the Cmax is increased 16-40%, the increase in mean AUC is
1388
approximately 30%, and can be at least partially attributed to decreased renal
1389
clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the
1390
elderly. These differences are not considered clinically significant. (See
1391
PRECAUTIONS: Geriatric Use.)
1392
1393
In patients with reduced renal function, the half-life of ciprofloxacin is slightly
1394
prolonged and dosage adjustments may be required. (See DOSAGE AND
1395
ADMINSTRATION.)
1396
1397
In preliminary studies in patients with stable chronic liver cirrhosis, no significant
1398
changes in ciprofloxacin pharmacokinetics have been observed. However, the
1399
kinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been
1400
fully elucidated.
1401
1402
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with
1403
50 mg/kg I.V. piperacillin sodium every four hours, mean serum ciprofloxacin
1404
concentrations were 3.02 µg/mL ½ hour and 1.18 µg/mL between 6-8 hours after
1405
the end of infusion.
1406
1407
The binding of ciprofloxacin to serum proteins is 20 to 40%.
1408
1409
After intravenous administration, ciprofloxacin is present in saliva, nasal and
1410
bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and
1411
prostatic secretions. It has also been detected in the lung, skin, fat, muscle,
1412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF
1413
concentrations are generally less than 10% of peak serum concentrations. Levels
1414
of the drug in the aqueous and vitreous chambers of the eye are lower than in
1415
serum.
1416
1417
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-
1418
negative and gram-positive microorganisms. The bactericidal action of
1419
ciprofloxacin results from interference with the enzyme DNA gyrase which is needed
1420
for the synthesis of bacterial DNA.
1421
1422
Ciprofloxacin has been shown to be active against most strains of the following
1423
microorganisms, both in vitro and in clinical infections as described in the
1424
INDICATIONS AND USAGE section of the package insert for CIPRO® I.V.
1425
(ciprofloxacin for intravenous infusion).
1426
1427
Aerobic gram-positive microorganisms
1428
Enterococcus faecalis (Many strains are only moderately susceptible.)
1429
Staphylococcus aureus (methicillin susceptible)
1430
Staphylococcus epidermidis
1431
Staphylococcus saprophyticus
1432
Streptococcus pneumoniae
1433
Streptococcus pyogenes
1434
1435
Aerobic gram-negative microorganisms
1436
Citrobacter diversus
Morganella morganii
1437
Citrobacter freundii
Proteus mirabilis
1438
Enterobacter cloacae
Proteus vulgaris
1439
Escherichia coli
Providencia rettgeri
1440
Haemophilus influenzae
Providencia stuartii
1441
Haemophilus parainfluenzae
Pseudomonas aeruginosa
1442
Klebsiella pneumoniae
Serratia marcescens
1443
Moraxella catarrhalis
1444
1445
Ciprofloxacin has been shown to be active against most strains of the following
1446
microorganisms, both in vitro and in clinical infections as described in the
1447
INDICATIONS AND USAGE section of the package insert for CIPRO®
1448
(ciprofloxacin hydrochloride) Tablets.
1449
1450
Aerobic gram-positive microorganisms
1451
1452
Enterococcus faecalis (Many strains are only moderately susceptible.)
1453
Staphylococcus aureus (methicillin susceptible)
1454
Staphylococcus epidermidis
1455
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
Staphylococcus saprophyticus
1456
Streptococcus pneumoniae
1457
Streptococcus pyogenes
1458
1459
Aerobic gram-negative microorganisms
1460
Campylobacter jejuni
Proteus mirabilis
1461
Citrobacter diversus
Proteus vulgaris
1462
Citrobacter freundii
Providencia rettgeri
1463
Enterobacter cloacae
Providencia stuartii
1464
Escherichia coli
Pseudomonas aeruginosa
1465
Haemophilus influenzae
Salmonella typhi
1466
Haemophilus parainfluenzae
Serratia marcescens
1467
Klebsiella pneumoniae
Shigella boydii
1468
Moraxella catarrhalis
Shigella dysenteriae
1469
Morganella morganii
Shigella flexneri
1470
Neisseria gonorrhoeae
Shigella sonnei
1471
1472
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro
1473
and by use of serum levels as a surrogate marker (see INDICATIONS AND
1474
USAGE and INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION).
1475
1476
The following in vitro data are available, but their clinical significance is
1477
unknown.
1478
1479
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL
1480
or less against most (>90%) strains of the following microorganisms; however, the
1481
safety and effectiveness of ciprofloxacin in treating clinical infections due to these
1482
microorganisms have not been established in adequate and well-controlled clinical
1483
trials.
1484
1485
Aerobic gram-positive microorganisms
1486
Staphylococcus haemolyticus
1487
Staphylococcus hominis
1488
1489
Aerobic gram-negative microorganisms
1490
Acinetobacter Iwoffi
Pasteurella multocida
1491
Aeromonas hydrophila
Salmonella enteritidis
1492
Edwardsiella tarda
Vibrio cholerae
1493
Enterobacter aerogenes
Vibrio parahaemolyticus
1494
Klebsiella oxytoca
Vibrio vulnificus
1495
Legionella pneumophila
Yersinia enterocolitica
1496
1497
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas
1498
maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including
1499
Bacteroides fragilis and Clostridium difficile.
1500
1501
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
1502
little effect when tested in vitro. The minimum bactericidal concentration (MBC)
1503
generally does not exceed the minimum inhibitory concentration (MIC) by more than
1504
a factor of two. Resistance to ciprofloxacin in vitro usually develops slowly (multiple-
1505
step mutation).
1506
1507
Ciprofloxacin does not cross-react with other antimicrobial agents such as beta-
1508
lactams or aminoglycosides; therefore, organisms resistant to these drugs may be
1509
susceptible to ciprofloxacin.
1510
1511
In vitro studies have shown that additive activity often results when ciprofloxacin is
1512
combined with other antimicrobial agents such as beta-lactams, aminoglycosides,
1513
clindamycin, or metronidazole. Synergy has been reported particularly with the
1514
combination of ciprofloxacin and a beta-lactam; antagonism is observed only rarely.
1515
1516
Susceptibility Tests
1517
Dilution Techniques: Quantitative methods are used to determine antimicrobial
1518
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
1519
susceptibility of bacteria to antimicrobial compounds. The MICs should be
1520
determined using a standardized procedure. Standardized procedures are based
1521
on a dilution method1 (broth or agar) or equivalent with standardized inoculum
1522
concentrations and standardized concentrations of ciprofloxacin powder. The MIC
1523
values should be interpreted according to the following criteria:
1524
1525
For testing aerobic microorganisms other than Haemophilus influenzae,
1526
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
1527
1528
MIC (µµg/mL)
Interpretation
1529
< 1
Susceptible (S)
1530
2
Intermediate (I)
1531
> 4
Resistant (R)
1532
1533
aThese interpretive standards are applicable only to broth microdilution
1534
susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with
1535
2-5% lysed horse blood.
1536
1537
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
1538
1539
MIC (µµg/mL) Interpretation
1540
< 1
Susceptible (S)
1541
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
1542
b This interpretive standard is applicable only to broth microdilution susceptibility
1543
tests with Haemophilus influenzae and Haemophilus parainfluenzae using
1544
Haemophilus Test Medium¹.
1545
1546
The current absence of data on resistant strains precludes defining any results other
1547
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible “
1548
category should be submitted to a reference laboratory for further testing.
1549
1550
For testing Neisseria gonorrhoeae
c:
1551
1552
MIC (µµg/mL) Interpretation
1553
< 0.06
Susceptible (S)
1554
1555
c This interpretive standard is applicable only to agar dilution test with GC agar base
1556
and 1% defined growth supplement.
1557
1558
The current absence of data on resistant strains precludes defining any results other
1559
than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible”
1560
category should be submitted to a reference laboratory for further testing.
1561
1562
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
1563
antimicrobial compound in the blood reaches the concentrations usually achievable.
1564
A report of “Intermediate” indicates that the result should be considered equivocal,
1565
and, if the microorganism is not fully susceptible to alternative, clinically feasible
1566
drugs, the test should be repeated. This category implies possible clinical
1567
applicability in body sites where the drug is physiologically concentrated or in
1568
situations where high dosage of drug can be used. This category also provides a
1569
buffer zone which prevents small uncontrolled technical factors from causing major
1570
discrepancies in interpretation. A report of “Resistant” indicates that the pathogen
1571
is not likely to be inhibited if the antimicrobial compound in the blood reaches the
1572
concentrations usually achievable; other therapy should be selected.
1573
1574
Standardized susceptibility test procedures require the use of laboratory control
1575
microorganisms to control the technical aspects of the laboratory procedures.
1576
Standard ciprofloxacin powder should provide the following MIC values:
1577
1578
Organism
MIC (µg/mL)
1579
1580
E. faecalis
ATCC 29212
0.25-2.0
1581
E. coli
ATCC 25922
0.004-0.015
1582
H. influenzae
a
ATCC 49247
0.004-0.03
1583
N. gonorrhoeae
b
ATCC 49226
0.001-0.008
1584
P. aeruginosa
ATCC 27853
0.25-1.0
1585
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
S. aureus
ATCC 29213
0.12-0.5
1586
1587
a This quality control range is applicable to only H. influenzae ATCC 49247 tested
1588
by a broth microdilution procedure using Haemophilus Test Medium (HTM)¹.
1589
1590
b This quality control range is applicable to only N. gonorrhoeae ATCC 49226
1591
tested by an agar dilution procedure using GC agar base and 1% defined growth
1592
supplement.
1593
1594
Diffusion Techniques: Quantitative methods that require measurement of zone
1595
diameters also provide reproducible estimates of the susceptibility of bacteria to
1596
antimicrobial compounds. One such standardized procedure2 requires the use
1597
of standardized inoculum concentrations. This procedure uses paper disks
1598
impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to
1599
ciprofloxacin.
1600
1601
Reports from the laboratory providing results of the standard single-disk
1602
susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to
1603
the following criteria:
1604
1605
For testing aerobic microorganisms other than Haemophilus influenzae,
1606
Haemophilus parainfluenzae, and Neisseria gonorrhoeae
a:
1607
1608
Zone Diameter (mm)
Interpretation
1609
>21
Susceptible (S)
1610
16-20
Intermediate (I)
1611
<15
Resistant (R)
1612
1613
a These zone diameter standards are applicable only to tests performed for
1614
streptococci using Mueller-Hinton agar supplemented with 5% sheep blood
1615
incubated in 5% CO2.
1616
1617
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b:
1618
1619
Zone Diameter(mm)
Interpretation
1620
>21
Susceptible (S)
1621
1622
b This zone diameter standard is applicable only to tests with Haemophilus
1623
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium
1624
(HTM)
2.
1625
1626
The current absence of data on resistant strains precludes defining any results other
1627
than “Susceptible”. Strains yielding zone diameter results suggestive of a
1628
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
“nonsusceptible” category should be submitted to a reference laboratory for further
1629
testing.
1630
For testing Neisseria gonorrhoeae
c:
1631
1632
Zone Diameter (mm)
Interpretation
1633
>36
Susceptible (S)
1634
1635
c This zone diameter standard is applicable only to disk diffusion tests with GC agar
1636
base and 1% defined growth supplement.
1637
1638
The current absence of data on resistant strains precludes defining any results other
1639
than “Susceptible”. Strains yielding zone diameter results suggestive of a
1640
“nonsusceptible” category should be submitted to a reference laboratory for further
1641
testing.
1642
1643
Interpretation should be as stated above for results using dilution techniques.
1644
Interpretation involves correlation of the diameter obtained in the disk test with the
1645
MIC for ciprofloxacin.
1646
1647
As with standardized dilution techniques, diffusion methods require the use of
1648
laboratory control microorganisms that are used to control the technical aspects of
1649
the laboratory procedures. For the diffusion technique, the 5-µg ciprofloxacin disk
1650
should provide the following zone diameters in these laboratory test quality control
1651
strains:
1652
1653
Organism
Zone Diameter (mm)
1654
E. coli
ATCC 25922
30-40
1655
H. influenzae
a
ATCC 49247
34-42
1656
N. gonorrhoeae
b
ATCC 49226
48-58
1657
P. aeruginosa
ATCC 27853
25-33
1658
S. aureus
ATCC 25923
22-30
1659
1660
aThese quality control limits are applicable to only H. influenzae ATCC 49247
1661
testing using Haemophilus Test Medium (HTM)².
1662
1663
b These quality control limits are applicable only to tests conducted with N.
1664
gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and
1665
1% defined growth supplement.
1666
1667
INDICATIONS AND USAGE
1668
1669
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
CIPRO® I.V. is indicated for the treatment of infections caused by susceptible
1670
strains of the designated microorganisms in the conditions listed below when the
1671
intravenous administration offers a route of administration advantageous to the
1672
patient. Please see DOSAGE AND ADMINISTRATION for specific
1673
recommendations.
1674
1675
Urinary Tract Infections caused by Escherichia coli (including cases with
1676
secondary bacteremia), Klebsiella pneumoniae subspecies pneumoniae,
1677
Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
1678
rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
1679
Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus
1680
saprophyticus, or Enterococcus faecalis.
1681
1682
Lower Respiratory Infections caused by Escherichia coli, Klebsiella
1683
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis,
1684
Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus
1685
parainfluenzae, or Streptococcus pneumoniae.
1686
1687
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
1688
the treatment of presumed or confirmed pneumonia secondary to Streptococcus
1689
pneumoniae.
1690
1691
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella
1692
pneumoniae.
1693
1694
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella
1695
pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis,
1696
Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii,
1697
Pseudomonas aeruginosa, Staphylococcus aureus (methicillin susceptible),
1698
Staphylococcus epidermidis, or Streptococcus pyogenes.
1699
1700
Bone and Joint Infections caused by Enterobacter cloacae, Serratia
1701
marcescens, or Pseudomonas aeruginosa.
1702
1703
Complicated Intra-Abdominal Infections (used in conjunction with
1704
metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
1705
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. (See DOSAGE AND
1706
ADMINSTRATION.)
1707
1708
Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae,
1709
or Moraxella catarrhalis.
1710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
1711
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
1712
1713
Empirical Therapy for Febrile Neutropenic Patients in combination with
1714
piperacillin sodium. (See DOSAGE AND ADMINISTRATION and CLINICAL
1715
STUDIES.)
1716
1717
Inhalational anthrax (post-exposure): To reduce the incidence or progression of
1718
disease following exposure to aerosolized Bacillus anthracis.
1719
1720
Ciprofloxacin serum concentrations achieved in humans serve as a surrogate
1721
endpoint reasonably likely to predict clinical benefit and provide the basis for this
1722
indication.
4 (See also, INHALATIONAL ANTHRAX – ADDITIONAL
1723
INFORMATION).
1724
1725
If anaerobic organisms are suspected of contributing to the infection, appropriate
1726
therapy should be administered.
1727
1728
Appropriate culture and susceptibility tests should be performed before treatment in
1729
order to isolate and identify organisms causing infection and to determine their
1730
susceptibility to ciprofloxacin. Therapy with CIPRO® I.V. may be initiated before
1731
results of these tests are known; once results become available, appropriate
1732
therapy should be continued.
1733
1734
As with other drugs, some strains of Pseudomonas aeruginosa may develop
1735
resistance fairly rapidly during treatment with ciprofloxacin. Culture and
1736
susceptibility testing performed periodically during therapy will provide information
1737
not only on the therapeutic effect of the antimicrobial agent but also on the possible
1738
emergence of bacterial resistance.
1739
1740
CLINICAL STUDIES
1741
1742
EMPIRICAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS
1743
1744
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with
1745
piperacillin sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile
1746
neutropenic patients were studied in one large pivotal multicenter, randomized trial
1747
and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with
1748
piperacillin sodium, 50 mg/kg I.V. q 4h.
1749
1750
The demographics of the evaluable patients were as follows:
1751
1752
Total
Ciprofloxacin/Piperacillin Tobramycin/Piperacillin
1753
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
N=233
N=237
1754
1755
Median Age (years)
47.0 (range 19-84)
50.0 (range 18-81)
1756
Male
114 (48.9%)
117 (49.4%)
1757
Female
119 (51.1%)
120 (50.6%)
1758
Leukemia/Bone Marrow
165 (70.8%)
158 (66.7%)
1759
Transplant
1760
Solid Tumor/Lymphoma
68 (29.2%)
79 (33.3%)
1761
Median Duration of
15.0 (range 1-61)
14.0 (range 1-89)
1762
Neutropenia (days)
1763
Clinical response rates observed in this study were as follows:
1764
1765
Outcomes
Ciprofloxacin/Piperacillin Tobramycin/Piperacillin
1766
N=233
N=237
1767
Success (%)
Success (%)
1768
1769
Clinical Resolution of
63 (27.0%)
52 (21.9%)
1770
Initial Febrile Episode with
1771
No Modifications of
1772
Empirical Regimen*
1773
1774
Clinical Resolution of
187 (80.3%)
185 (78.1%)
1775
Initial Febrile Episode
1776
Including Patients with
1777
Modifications of
1778
Empirical Regimen
1779
1780
Overall Survival 224 (96.1%)
223 (94.1%)
1781
1782
*To be evaluated as a clinical resolution, patients had to have: (1) resolution of
1783
fever; (2) microbiological eradication of infection (if an infection was
1784
microbiologically documented); (3) resolution of signs/symptoms of infection; and
1785
(4) no modification of empirical antibiotic regimen.
1786
1787
CONTRAINDICATIONS
1788
1789
CIPRO® I.V. (ciprofloxacin) is contraindicated in persons with history of
1790
hypersensitivity to ciprofloxacin or any member of the quinolone class of
1791
antimicrobial agents.
1792
1793
WARNINGS
1794
1795
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC
1796
PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), , -
1797
EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE),
1798
PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN
1799
ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and
1800
Nursing Mothers subsections.) Ciprofloxacin causes lameness in immature dogs.
1801
Histopathological examination of the weight-bearing joints of these dogs revealed
1802
permanent lesions of the cartilage. Related quinolone-class drugs also produce
1803
erosions of cartilage of weight-bearing joints and other signs of arthropathy in
1804
immature animals of various species. (See ANIMAL PHARMACOLOGY.)
1805
1806
Convulsions, increased intracranial pressure and toxic psychosis have been
1807
reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may
1808
also cause central nervous system (CNS) events including: dizziness, confusion,
1809
tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These
1810
reactions may occur following the first dose. If these reactions occur in patients
1811
receiving ciprofloxacin, the drug should be discontinued and appropriate measures
1812
instituted. As with all quinolones, ciprofloxacin should be used with caution in
1813
patients with known or suspected CNS disorders that may predispose to seizures
1814
or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in
1815
the presence of other risk factors that may predispose to seizures or lower the
1816
seizure threshold (e.g. certain drug therapy, renal dysfunction). (See
1817
PRECAUTIONS: General, Information for Patients, Drug Interaction and
1818
ADVERSE REACTIONS.)
1819
1820
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
1821
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
1822
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included
1823
cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar
1824
serious adverse events have been reported in patients receiving theophylline alone,
1825
the possibility that these reactions may be potentiated by ciprofloxacin cannot be
1826
eliminated. If concomitant use cannot be avoided, serum levels of theophylline
1827
should be monitored and dosage adjustments made as appropriate.
1828
1829
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some
1830
following the first dose, have been reported in patients receiving quinolone therapy.
1831
Some reactions were accompanied by cardiovascular collapse, loss of
1832
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.
1833
Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic
1834
reactions require immediate emergency treatment with epinephrine and other
1835
resuscitation measures, including oxygen, intravenous fluids, intravenous
1836
antihistamines, corticosteroids, pressor amines, and airway management, as
1837
clinically indicated.
1838
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
1839
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia,
1840
jaundice, and hepatic necrosis with fatal outcome have also been reported
1841
extremely rarely in patients receiving ciprofloxacin along with other drugs. The
1842
possibility that these reactions were related to ciprofloxacin cannot be excluded.
1843
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any
1844
other sign of hypersensitivity.
1845
1846
Pseudomembranous colitis has been reported with nearly all antibacterial
1847
agents, including ciprofloxacin, and may range in severity from mild to life-
1848
threatening. Therefore, it is important to consider this diagnosis in patients
1849
who present with diarrhea subsequent to the administration of antibacterial
1850
agents.
1851
1852
Treatment with antibacterial agents alters the normal flora of the colon and may
1853
permit overgrowth of clostridia. Studies indicate that a toxin produced by
1854
Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
1855
1856
After the diagnosis of pseudomembranous colitis has been established, therapeutic
1857
measures should be initiated. Mild cases of pseudomembranous colitis usually
1858
respond to drug discontinuation alone. In moderate to severe cases, consideration
1859
should be given to management with fluids and electrolytes, protein
1860
supplementation, and treatment with an antibacterial drug clinically effective against
1861
C. difficile colitis.
1862
1863
Achilles and other tendon ruptures that required surgical repair or resulted in
1864
prolonged disability have been reported with ciprofloxacin and other quinolones.
1865
Ciprofloxacin should be discontinued if the patient experiences pain, inflammation,
1866
or rupture of a tendon.
1867
1868
PRECAUTIONS
1869
1870
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINSTERED BY
1871
SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions
1872
have been reported with the intravenous administration of ciprofloxacin. These
1873
reactions are more frequent if infusion time is 30 minutes or less or if small veins of
1874
the hand are used. (See ADVERSE REACTIONS.)
1875
1876
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS)
1877
events, including: nervousness, agitation, insomnia, anxiety, nightmares or
1878
paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)
1879
1880
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects
1881
but more frequently in the urine of laboratory animals, which is usually alkaline. (See
1882
ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been
1883
reported only rarely in humans because human urine is usually acidic. Alkalinity of
1884
the urine should be avoided in patients receiving ciprofloxacin. Patients should be
1885
well hydrated to prevent the formation of highly concentrated urine.
1886
1887
Alteration of the dosage regimen is necessary for patients with impairment of renal
1888
function. (See DOSAGE AND ADMINSTRATION.)
1889
1890
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction
1891
has been observed in some patients who were exposed to direct sunlight while
1892
receiving some members of the quinolone class of drugs. Excessive sunlight
1893
should be avoided.
1894
1895
As with any potent drug, periodic assessment of organ system functions, including
1896
renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
1897
1898
Information For Patients: Patients should be advised that ciprofloxacin may be
1899
associated with hypersensitivity reactions, even following a single dose, and to
1900
discontinue the drug at the first sign of a skin rash or other allergic reaction.
1901
1902
Ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should
1903
know how they react to this drug before they operate an automobile or machinery or
1904
engage in activities requiring mental alertness or coordination.
1905
1906
Patients should be advised that ciprofloxacin may increase the effects of
1907
theophylline and caffeine. There is a possibility of caffeine accumulation when
1908
products containing caffeine are consumed while taking ciprofloxacin.
1909
1910
Patients should be advised to discontinue treatment; rest and refrain from exercise;
1911
and inform their physician if they experience pain, inflammation, or rupture of a
1912
tendon.
1913
1914
Patients should be advised that convulsions have been reported in patients taking
1915
quinolones, including ciprofloxacin, and to notify their physician before taking this
1916
drug if there is a history of this condition.
1917
1918
Drug Interactions: As with some other quinolones, concurrent administration of
1919
ciprofloxacin with theophylline may lead to elevated serum concentrations of
1920
theophylline and prolongation of its elimination half-life. This may result in increased
1921
risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
1922
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
use cannot be avoided, serum levels of theophylline should be monitored and
1923
dosage adjustments made as appropriate.
1924
1925
Some quinolones, including ciprofloxacin, have also been shown to interfere with the
1926
metabolism of caffeine. This may lead to reduced clearance of caffeine and
1927
prolongation of its serum half-life.
1928
1929
Some quinolones, including ciprofloxacin, have been associated with transient
1930
elevations in serum creatinine in patients receiving cyclosporine concomitantly.
1931
1932
Altered serum levels of phenytoin (increased and decreased) have been reported in
1933
patients receiving concomitant ciprofloxacin.
1934
1935
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has,
1936
in some patients, resulted in severe hypoglycemia. Fatalities have been reported.
1937
1938
Quinolones have been reported to enhance the effects of the oral anticoagulant
1939
warfarin or its derivatives. When these products are administered concomitantly,
1940
prothrombin time or other suitable coagulation tests should be closely monitored.
1941
1942
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an
1943
increase in the level of ciprofloxacin in the serum. This should be considered if
1944
patients are receiving both drugs concomitantly.
1945
1946
As with other broad-spectrum antimicrobial agents, prolonged use of ciprofloxacin
1947
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the
1948
patient’s condition and microbial susceptibility testing are essential. If
1949
superinfection occurs during therapy, appropriate measures should be taken.
1950
1951
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro
1952
mutagenicity tests have been conducted with ciprofloxacin. Test results are listed
1953
below:
1954
1955
Salmonella/Microsome Test (Negative)
1956
E. coli DNA Repair Assay (Negative)
1957
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
1958
Chinese Hamster V79 Cell HGPRT Test (Negative)
1959
Syrian Hamster Embryo Cell Transformation Assay (Negative)
1960
Saccharomyces cerevisiae Point Mutation Assay (Negative)
1961
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay
1962
(Negative)
1963
Rat Hepatocyte DNA Repair Assay (Positive)
1964
1965
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
Thus, two of the eight tests were positive, but results of the following three in vivo
1966
test systems gave negative results:
1967
1968
Rat Hepatocyte DNA Repair Assay
1969
Micronucleus Test (Mice)
1970
Dominant Lethal Test (Mice)
1971
1972
Long-term carcinogenicity studies in mice and rats have been completed. After
1973
daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up
1974
to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or
1975
tumorigenic effects in these species.
1976
1977
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not
1978
reduce the time to appearance of UV-induced skin tumors as compared to vehicle
1979
control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times
1980
every two weeks for up to 78 weeks while concurrently being administered
1981
ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
1982
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal
1983
to maximum recommended human dose based upon mg/m
2), as opposed to 34
1984
weeks when animals were treated with both UVA and vehicle. The times to
1985
development of skin tumors ranged from 16-32 weeks in mice treated concomitantly
1986
with UVA and other quinolones.
3
1987
1988
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic
1989
tumors. There are no data from similar models using pigmented mice and/or fully
1990
haired mice. The clinical significance of these findings to humans is unknown.
1991
1992
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (0.8
1993
times the highest recommended human dose of 1200 mg based upon body surface
1994
area) revealed no evidence of impairment.
1995
1996
Pregnancy: Teratogenic Effects. Pregnancy Category C: Reproduction
1997
studies have been performed in rats and mice using oral doses of up to 100mg/kg
1998
(0.8 and 0.4 times the maximum daily human dose based upon body surface area,
1999
respectively) and I.V. doses of up to 30 mg/kg (0.24 and 0.12 times the maximum
2000
daily human dose based upon body surface area, respectively) and have revealed
2001
no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30
2002
and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal
2003
weight loss and an increased incidence of abortion, but no teratogenicity was
2004
observed at either dose. After intravenous administration of doses up to 20 mg/kg,
2005
no maternal toxicity was produced in the rabbit, and no embryotoxicity or
2006
teratogenicity was observed. There are, however, no adequate and well-controlled
2007
studies in pregnant women. Ciprofloxacin should be used during pregnancy only if
2008
the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)
2009
2010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Nursing Mothers: Ciprofloxacin is excreted in human milk. Because of the
2011
potential for serious adverse reactions in infants nursing from mothers taking
2012
ciprofloxacin, a decision should be made whether to discontinue nursing or to
2013
discontinue the drug, taking into account the importance of the drug to the mother.
2014
2015
Pediatric Use: Safety and effectiveness in pediatric patients and adolescents less
2016
than 18 years of age have not been established, except for use in inhalational
2017
anthrax (post-exposure). Ciprofloxacin causes arthropathy in juvenile animals. (See
2018
WARNINGS.)
2019
2020
For the indication of inhalational anthrax (post-exposure), the risk-benefit
2021
assessment indicates that administration of ciprofloxacin to pediatric patients is
2022
appropriate. For information regarding pediatric dosing in inhalational anthrax
2023
(post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL
2024
ANTHRAX – ADDITIONAL INFORMATION.
2025
2026
Short-term safety data from a single trial in pediatric cystic fibrosis patients are
2027
available. In a randomized, double-blind clinical trial for the treatment of acute
2028
pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients
2029
received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by
2030
ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
2031
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and
2032
tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 - 21 days. Patients less than 5
2033
years of age were not studied. Safety monitoring in the study included periodic
2034
range of motion examinations and gait assessments by treatment-blinded
2035
examiners. Patients were followed for an average of 23 days after completing
2036
treatment (range 0-93 days). This study was not designed to determine long term
2037
effects and the safety of repeated exposure to ciprofloxacin.
2038
2039
In the study, injection site reactions were more common in the ciprofloxacin group
2040
(24%) than in the comparison group (8%). Other adverse events were similar in
2041
nature and frequency between treatment arms. Musculoskeletal adverse events
2042
were reported in 22% of the patients in the ciprofloxacin group and 21% in the
2043
comparison group. Decreased range of motion was reported in 12% of the
2044
subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia
2045
was reported in 10% of the patients in the ciprofloxacin group and 11% in the
2046
comparison group. One of sixty-seven patients developed arthritis of the knee nine
2047
days after a ten day course of treatment with ciprofloxacin. Clinical symptoms
2048
resolved, but an MRI showed knee effusion without other abnormalities eight months
2049
after treatment. However, the relationship of this event to the patient’s course of
2050
ciprofloxacin can not be definitively determined, particularly since patients with
2051
cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease
2052
process.
2053
2054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
Geriatric Use: In a retrospective analysis of 23 multiple-dose controlled clinical
2055
trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25%
2056
of patients were greater than or equal to 65 years of age and 10% were greater
2057
than or equal to 75 years of age. No overall differences in safety or effectiveness
2058
were observed between these subjects and younger subjects, and other reported
2059
clinical experience has not identified differences in responses between the elderly
2060
and younger patients, but greater sensitivity of some older individuals on any drug
2061
therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by
2062
the kidney, and the risk of adverse reactions may be greater in patients with
2063
impaired renal function. No alteration of dosage is necessary for patients greater
2064
than 65 years of age with normal renal function. However, since some older
2065
individuals experience reduced renal function by virtue of their advanced age, care
2066
should be taken in dose selection for elderly patients, and renal function monitoring
2067
may be useful in these patients. (See CLINICAL PHARMACOLOGY and
2068
DOSAGE AND ADMINISTATION.)
2069
2070
ADVERSE REACTIONS
2071
2072
The most frequently reported events, without regard to drug relationship, among
2073
patients treated with intravenous ciprofloxacin were nausea, diarrhea, central
2074
nervous system disturbance, local I.V. site reactions, abnormalities of liver
2075
associated enzymes (hepatic enzymes), and eosinophilia. Headache,
2076
restlessness, and rash were also noted in greater than 1% of patients treated with
2077
the most common doses of ciprofloxacin.
2078
2079
Local I.V. site reactions have been reported with the intravenous administration of
2080
ciprofloxacin. These reactions are more frequent if the infusion time is 30 minutes
2081
or less. These may appear as local skin reactions which resolve rapidly upon
2082
completion of the infusion. Subsequent intravenous administration is not
2083
contraindicated unless the reactions recur or worsen.
2084
2085
Additional events, without regard to drug relationship or route of administration, that
2086
occurred in 1% or less of ciprofloxacin patients are listed below:
2087
2088
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest,
2089
myocardial infarction, arrhythmia, tachycardia, palpitation, cerebral
2090
thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina
2091
pectoris
2092
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic
2093
psychosis, depression, dysphasia, phobia, depersonalization, manic
2094
reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness,
2095
lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
2096
weakness, drowsiness, irritability, malaise, lethargy
2097
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile
2098
associated diarrhea, pseudomembranous colitis, pancreatitis, hepatic
2099
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
necrosis, intestinal perforation, dyspepsia, epigastric or abdominal pain,
2100
vomiting, constipation, oral ulceration, oral candidiasis, mouth dryness,
2101
anorexia, dysphagia, flatulence
2102
I.V. INFUSION SITE: thrombophlebitis, burning, pain, pruritus, paresthesia,
2103
erythema, swelling
2104
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck
2105
and chest pain, achiness, flare up of gout
2106
RENAL/UROGENITAL: renal failure, interstitial nephritis, hemorrhagic
2107
cystitis, renal calculi, frequent urination, acidosis, urethral bleeding, polyuria,
2108
urinary retention, gynecomastia, candiduria, vaginitis. Crystalluria,
2109
cylindruria, hematuria and albuminuria have also been reported.
2110
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea,
2111
pulmonary edema, respiratory distress, pleural effusion, hemoptysis,
2112
epistaxis, hiccough
2113
SKIN/HYPERSENSITIVITY: anaphylactic reactions, erythema
2114
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
2115
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck,
2116
conjunctivae, hands or lower extremities, purpura, fever, chills, flushing,
2117
pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration,
2118
hyperpigmentation, erythema nodosum, photosensitivity
2119
(See WARNINGS.)
2120
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision
2121
(flashing lights, change in color perception, overbrightness of lights,
2122
diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, a bad taste
2123
2124
Also reported were agranulocytosis, prolongation of prothrombin time, and
2125
possible exacerbation of myasthenia gravis.
2126
2127
Many of these events were described as only mild or moderate in severity,
2128
abated soon after the drug was discontinued, and required no treatment.
2129
2130
In several instances, nausea, vomiting, tremor, irritability, or palpitation were
2131
judged by investigators to be related to elevated serum levels of theophylline
2132
possibly as a result of drug interaction with ciprofloxacin.
2133
2134
In randomized, double-blind controlled clinical trials comparing ciprofloxacin
2135
(I.V. and I.V. P.O. sequential) with intravenous beta-lactam control antibiotics,
2136
the CNS adverse event profile of ciprofloxacin was comparable to that of the
2137
control drugs.
2138
2139
Post-Marketing Adverse Events: Additional adverse events, regardless of
2140
relationship to drug, reported from worldwide marketing experience with
2141
quinolones, including ciprofloxacin, are:
2142
2143
BODY AS A WHOLE: change in serum phenytoin
2144
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
CARDIOVASCULAR: postural hypotension, vasculitis
2145
CENTRAL NERVOUS SYSTEM: agitation, delirium,
2146
myoclonus, toxic psychosis
2147
HEMIC/LYMPHATIC: hemolytic anemia, methemoglobinemia
2148
METABOLIC/NUTRITIONAL: elevation of serum triglycerides,
2149
cholesterol, blood glucose, serum potassium
2150
MUSCULOSKELETAL: myalgia, tendinitis/tendon rupture
2151
RENAL/UROGENITAL: vaginal candidiasis
2152
(See PRECAUTIONS.)
2153
2154
Adverse Laboratory Changes: The most frequently reported changes in
2155
laboratory parameters with intravenous ciprofloxacin therapy, without regard to drug
2156
relationship are listed below:
2157
2158
Hepatic - elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase,
2159
LDH, and serum bilirubin;
2160
Hematologic - elevated eosinophil and platelet counts, decreased platelet
2161
counts, hemoglobin and/or hematocrit;
2162
Renal -
elevations of serum creatinine, BUN, and uric acid;
2163
Other -
elevations of serum creatinine phosphokinase, serum theophylline
2164
(in patients receiving theophylline concomitantly), blood glucose,
2165
and triglycerides.
2166
2167
Other changes occurring infrequently were: decreased leukocyte count, elevated
2168
atypical lymphocyte count, immature WBCs, elevated serum calcium, elevation of
2169
serum gamma-glutamyl transpeptidase (gamma GT), decreased BUN, decreased
2170
uric acid, decreased total serum protein, decreased serum albumin, decreased
2171
serum potassium, elevated serum potassium, elevated serum cholesterol.
2172
2173
Other changes occurring rarely during administration of ciprofloxacin were: elevation
2174
of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated
2175
sedimentation rate, change in serum phenytoin, decreased prothrombin time,
2176
hemolytic anemia, and bleeding diathesis.
2177
2178
OVERDOSAGE
2179
2180
In the event of acute overdosage, the patient should be carefully observed and given
2181
supportive treatment. Adequate hydration must be maintained. Only a small
2182
amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or
2183
peritoneal dialysis.
2184
2185
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions
2186
was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
2187
2188
DOSAGE AND ADMINSTRATION
2189
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
2190
The recommended adult dosage for urinary tract infections of mild to moderate
2191
severity is 200 mg I.V every 12 hours. For severe or complicated urinary tract
2192
infections, the recommended dosage is 400 mg I.V. every 12 hours.
2193
2194
The recommended adult dosage for lower respiratory tract infections, skin and skin
2195
structure infections, and bone and joint infections of mild to moderate severity is 400
2196
mg I.V. every 12 hours.
2197
2198
For severe/complicated infections of the lower respiratory tract, skin and skin
2199
structure, and bone and joint, the recommended adult dosage is 400 mg I.V. every 8
2200
hours.
2201
2202
The recommended adult dosage for mild, moderate, and severe nosocomial
2203
pneumonia is 400 mg I.V. every 8 hours.
2204
2205
Complicated Intra-Abdominal Infections: Sequential therapy [parenteral to oral -
2206
400 mg CIPRO® I.V. q12h (plus I.V. metronidazole) è 500 mg CIPRO® Tablets
2207
q12h (plus oral metronidazole)] can be instituted at the discretion of the physician.
2208
Metronidazole should be given according to product labeling to provide appropriate
2209
anaerobic coverage.
2210
2211
The recommended dosage for mild to moderate Acute Sinusitis and Chronic
2212
Bacterial Prostatitis is 400 mg I.V. every 12 hours.
2213
2214
The recommended adult dosage for empirical therapy of febrile neutropenic
2215
patients is 400 mg I.V. every 8 hours in combination with piperacillin sodium 50
2216
mg/kg I.V. q 4 hours, not to exceed 24 g/day (300 mg/kg/day), for 7-14 days.
2217
2218
The determination of dosage for any particular patient must take into consideration
2219
the severity and nature of the infection, the susceptibility of the causative
2220
microorganism, the integrity of the patient’s host-defense mechanisms, and the
2221
status of renal and hepatic function.
2222
2223
DOSAGE GUIDELINES
Intravenous
InfectionU
U
Type or Severity
Unit Dose
Frequency
Daily Dose
Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
400 mg
800 mg
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
1200 mg
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
800 mg
1200 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
Intra-Abdominal*
Complicated
400 mg
q12h
800 mg
Acute Sinusitis
Mild/Moderate
400 mg
q12h
800 mg
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
800 mg
Empirical Therapy in
Febrile Neutropenic
Patients
Severe
Ciprofloxacin
+
Piperacillin
400 mg
50 mg/kg
q8h
q4h
1200 mg
Not to exceed
24 g/day
Inhalational anthrax
(post-exposure) **
Adult
Pediatric
400 mg
10 mg/kg per dose, not
to exceed 400 mg per
dose
q12h
q12h
800 mg
Not to exceed 800
mg
* used in conjunction with metronidazole. (See product labeling for prescribing information.)
UDUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
** Drug administration should begin as soon as possible after suspected or confirmed
exposure. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations
achieved in humans. For a discussion of ciprofloxacin serum concentrations in various human
populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION. Total duration of
ciprofloxacin administration (IV or oral) for inhalational anthrax (post-exposure) is 60 days.
2224
CIPRO® I.V. should be administered by intravenous infusion over a period
2225
of 60 minutes.
2226
2227
Parenteral drug products should be inspected visually for particulate matter and
2228
discoloration prior to administration.
2229
2230
Ciprofloxacin hydrochloride (CIPRO® Tablets) for oral administration are available.
2231
Parenteral therapy may be changed to oral CIPRO® Tablets when the condition
2232
warrants, at the discretion of the physician. For complete dosage and
2233
administration information, see CIPRO® Tablets package insert.
2234
2235
Impaired Renal Function: The following table provides dosage guidelines for use
2236
in patients with renal impairment; however, monitoring of serum drug levels provides
2237
the most reliable basis for dosage adjustment.
2238
2239
RECOMMENDED STARTING AND MAINTENANCE DOSES
2240
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
2241
2242
Creatinine Clearance (mL/min)
Dosage
2243
>30
See usual dosage.
2244
5-29
200-400 mg q 18-24 hr
2245
2246
When only the serum creatinine concentration is known, the following formula may
2247
be used to estimate creatinine clearance:
2248
2249
Men: Creatinine clearance (mL/min) = Weight (kg) x (140 - age)
2250
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
72 x serum creatinine (mg/dL)
2251
Women: 0.85 x the value calculated for men.
2252
2253
The serum creatinine should represent a steady state of renal function.
2254
2255
For patients with changing renal function or for patients with renal impairment and
2256
hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will
2257
provide additional guidance for adjusting dosage.
2258
2259
INTRAVENOUS ADMINISTRATION
2260
2261
CIPRO® I.V. should be administered by intravenous infusion over a period of 60
2262
minutes. Slow infusion of a dilute solution into a larger vein will minimize patient
2263
discomfort and reduce the risk of venous irritation.
2264
2265
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED
2266
BEFORE USE. The intravenous dose should be prepared by aseptically
2267
withdrawing the concentrate from the vial of CIPRO® I.V. This should be diluted with
2268
a suitable intravenous solution to a final concentration of 1-2mg/mL. (See
2269
COMPATIBILITY AND STABILITY.) The resulting solution should be infused over
2270
a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set
2271
which may already be in place.
2272
2273
If this method or the “piggyback” method of administration is used, it is advisable to
2274
discontinue temporarily the administration of any other solutions during the infusion
2275
of CIPRO® I.V.
2276
2277
Flexible Containers: CIPRO® I.V. is also available as a 0.2% premixed solution in
2278
5% dextrose in flexible containers of 100 mL or 200 mL. The solutions in flexible
2279
containers may be infused as described above.
2280
2281
COMPATIBILITY AND STABILITY
2282
2283
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous
2284
solutions to concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at
2285
refrigerated or room temperature storage.
2286
0.9% Sodium Chloride Injection, USP
2287
5% Dextrose Injection, USP
2288
Sterile Water for Injection
2289
10% Dextrose for Injection
2290
5% Dextrose and 0.225% Sodium Chloride for Injection
2291
5% Dextrose and 0.45% Sodium Chloride for Injection
2292
Lactated Ringer’s for Injection
2293
2294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
If CIPRO® I.V. is to be given concomitantly with another drug, each drug should be
2295
given separately in accordance with the recommended dosage and route of
2296
administration for each drug.
2297
2298
2299
HOW SUPPLIED
2300
2301
CIPRO® I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish
2302
solution. CIPRO® I.V. is available in 200 mg and 400 mg strengths. The
2303
concentrate is supplied in vials while the premixed solution is supplied in flexible
2304
containers as follows:
2305
2306
VIAL:
SIZE
STRENGTH
NDC NUMBER
2307
20 mL
200 mg, 1%
0026-8562-20
2308
40 mL
400 mg, 1%
0026-8564-64
2309
2310
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Abbott
2311
Laboratories, North Chicago, IL 60064.
2312
SIZE
STRENGTH
NDC NUMBER
2313
100 mL 5% Dextrose
200 mg, 0.2%
0026-8552-36
2314
200 mL 5% Dextrose
400 mg, 0.2%
0026-8554-63
2315
2316
FLEXIBLE CONTAINER: manufactured for Bayer Corporation by Baxter
2317
Healthcare Corporation, Deerfield, IL 60015.
2318
SIZE
STRENGTH
NDC NUMBER
2319
100 mL 5% Dextrose
200 mg, 0.2%
0026-8527-36
2320
200 mL 5% Dextrose
400 mg, 0.2%
0026-8527-63
2321
2322
STORAGE
2323
Vial:
Store between 5-30oC (41-86oF).
2324
Flexible Container:
Store between 5-25oC (41-77oF).
2325
2326
Protect from light, avoid excessive heat, protect from freezing.
2327
2328
CIPRO® I.V. (ciprofloxacin) is also available in a 120 mL Pharmacy Bulk Package.
2329
2330
Ciprofloxacin is also available as CIPRO® (ciprofloxacin HCI) Tablets 100, 250,
2331
500, and 750 mg and CIPRO® (ciprofloxacin) 5% and 10% Oral Suspension.
2332
2333
ANIMAL PHARMACOLOGY
2334
2335
Ciprofloxacin and other quinolones have been shown to cause arthropathy in
2336
immature animals of most species tested. (See WARNINGS.) Damage of weight-
2337
bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
2338
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
ciprofloxacin given daily for 4 weeks caused degenerative articular changes of the
2339
knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study
2340
in beagles, removal of weight-bearing from the joint reduced the lesions but did not
2341
totally prevent them.
2342
2343
Crystalluria, sometimes associated with secondary nephropathy, occurs in
2344
laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced
2345
solubility of ciprofloxacin under alkaline conditions, which predominate in the urine
2346
of test animals; in man, crystalluria is rare since human urine is typically acidic. In
2347
rhesus monkeys, crystalluria without nephropathy has been noted after intravenous
2348
doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no
2349
nephropathological changes were noted; however, nephropathy was observed after
2350
dosing at 20 mg/kg/day for the same duration.
2351
2352
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection
2353
(15 sec.) produces pronounced hypotensive effects. These effects are considered
2354
to be related to histamine release because they are partially antagonized by
2355
pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also
2356
produces hypotension, but the effect in this species is inconsistent and less
2357
pronounced.
2358
2359
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as
2360
phenylbutazone and indomethacin, with quinolones has been reported to enhance
2361
the CNS stimulatory effect of quinolones.
2362
2363
Ocular toxicity, seen with some related drugs, has not been observed in
2364
ciprofloxacin-treated animals.
2365
2366
2367
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
2368
2369
The mean serum concentrations of ciprofloxacin associated with a statistically
2370
significant improvement in survival in the rhesus monkey model of inhalational
2371
anthrax are reached or exceeded in adult and pediatric patients receiving oral and
2372
intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin
2373
pharmacokinetics have been evaluated in various human populations. The mean
2374
peak serum concentration achieved at steady state in human adults receiving 500
2375
mg orally every 12 hours is 2.97 µg/ml, and 4.56 µg/ml following 400 mg
2376
intravenously every 12 hours. The mean trough serum concentration at steady state
2377
for both of these regimens is 0.2 µg/ml. In a study of 10 pediatric patients between 6
2378
and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL
2379
and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute
2380
intravenous infusions of 10 mg/kg administered 12 hours apart. After the second
2381
intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a
2382
mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety
2383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
data, including effects on cartilage, following the administration of ciprofloxacin to
2384
pediatric patients are limited. (For additional information, see PRECAUTIONS,
2385
Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
2386
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis
2387
for this indication.
4
2388
2389
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
2390
dose of 11 LD50 (~5.5 x 105) spores (range 5-30 LD50) of B. anthracis was
2391
conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the
2392
anthrax strain used in this study was 0.08 µg/ml. In the animals studied, mean serum
2393
concentrations of ciprofloxacin achieved at expected Tmax
2394
(1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69
2395
µg/ml. Mean steady state trough concentrations at 12 hours post-dose ranged from
2396
0.12 to 0.19 µg/ml
5. Mortality due to anthrax for animals that received a 30-day
2397
regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly
2398
lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
2399
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug
2400
administration period.
6
2401
2402
References:
2403
1. National Committee for Clinical Laboratory Standards, Methods for Dilution
2404
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition.
2405
Approved Standard NCCLS Document M7- A5, Vol. 20, No. 2, NCCLS, Wayne,
2406
PA, January, 2000.
2407
2. National Committee for Clinical Laboratory Standards, Performance Standards
2408
for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard
2409
NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
2410
3. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug
2411
Products Advisory Committee Meeting, March 31, 1993, Silver Spring MD. Report
2412
available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901
2413
Chapman Avenue, Room 200, Rockville, MD 20852, USA
2414
4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-
2415
Threatening Illnesses)
2416
5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin
2417
during prolonged therapy in rhesus monkeys J Infect Dis 1992; 166: 1184-7.
2418
6. Friedlander AM, et al. Postexposure prophylaxis against experimental
2419
inhalational anthrax J Infect Dis 1993; 167: 1239-42.
2420
2421
2422
2423
Bayer Corporation
2424
Pharmaceutical Division
2425
400 Morgan Lane
2426
West Haven, CT 06516 USA
2427
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
58
2428
BAYER
2429
Rx Only
2430
2431
PZXXXXXX 8/00 BAY q 3939
5202-4-A-U.S.-7 ©2000 Bayer Corporation
2432
XXXX
2433
Printed in U.S.A.
2434
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:11.407258
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20780S08lbl.pdf', 'application_number': 19858, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
11,795
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CIPRO
IV safely and effectively. See full prescribing information for CIPRO IV.
CIPRO IV® (ciprofloxacin) injection, for intravenous use
Initial U.S. Approval: 1987
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING
TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY,
CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION
OF MYASTHENIA GRAVIS
See full prescribing information for complete boxed warning.
•
Fluoroquinolones, including CIPRO IV®, have been associated
with disabling and potentially irreversible serious adverse
reactions that have occurred together (5.1), including:
o Tendinitis and tendon rupture (5.2)
o Peripheral neuropathy (5.3)
o Central nervous system effects (5.4)
Discontinue CIPRO immediately and avoid the use of
fluoroquinolones, including CIPRO, in patients who experience any
of these serious adverse reactions (5.1)
• Fluoroquinolones, including CIPRO IV, may exacerbate muscle
weakness in patients with myasthenia gravis. Avoid CIPRO IV in
patients with known history of myasthenia gravis. (5.5)
• Because fluoroquinolones, including CIPRO, have been associated
with serious adverse reactions (5.1-5.15), reserve CIPRO for use in
patients who have no alternative treatment options for the following
indications:
o Acute exacerbation of chronic bronchitis (1.9)
o Acute sinusitis (1.11)
-------------------------- RECENT MAJOR CHANGES -------------------------
Boxed Warning
X/2016
Indications and Usage (1.9, 1.11)
X/2016
Dosage and Administration, Dosage in Adults (2.1)
X/2016
Warnings and Precautions (5)
X/2016
--------------------------- INDICATIONS AND USAGE -------------------------
CIPRO IV is a fluoroquinolone antibacterial indicated in adults (≥18 years of
age) with the following infections caused by designated, susceptible bacteria
and in pediatric patients where indicated:
•
Skin and Skin structure Infections (1.1)
•
Bone and Joint infections (1.2)
•
Complicated Intra-Abdominal infections (1.3)
•
Nosocomial Pneumonia (1.4)
•
Empirical Therapy for Febrile Neutropenic Patients (1.5)
•
Inhalational Anthrax Post-Exposure in Adult and Pediatric Patients (1.6)
•
Plague in adult and pediatric patients (1.7)
•
Chronic Bacterial Prostatitis (1.8)
•
Lower respiratory tract infections (1.9)
o Acute Exacerbation of Chronic Bronchitis
•
Urinary Tract Infections (1.10)
o Urinary Tract Infections (UTI)
o Complicated UTI and Pyelonephritis in Pediatric Patients
•
Acute Sinusitis (1.11)
Usage
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV should be
used only to treat or prevent infections that are proven or strongly suspected to
be caused by bacteria. (1.12)
---------------------- DOSAGE AND ADMINISTRATION ---------------------
Adult Dosage Guidelines
Infection
Dose
Frequency
Duration
Skin and Skin Structure
400 mg
every 8 to 12 hours
7–14 days
Bone and Joint
400 mg
every 8 to 12 hours 4 to 8 weeks
Complicated Intra-Abdominal
400 mg
every 12 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Empirical Therapy In Febrile
Neutropenic Patients
400 mg
and
every 8 hours
Piperacillin
50 mg/kg
every 4 hours
7–14 days
Inhalational anthrax(post
exposure)
400 mg
every 12 hours
60 days
Plague
400 mg
every 8 to 12 hours
14 days
Chronic Bacterial prostatitis
400 mg
every 12 hours
28 days
Lower Respiratory Tract
400 mg
every 8 to 12 hours
7–14 days
Urinary Tract
200 to
400 mg
every 8 to 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
•
Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h (2.3)
Pediatric Intravenous Dosing Guidelines
Infection
Dose
Frequency
Duration
Complicated UTI and
Pyelonephritis
(patients from 1 to 17
years of age)
6 mg/kg to 10 mg/kg
(maximum 400 mg
per dose)
Every 8
hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)
10 mg/kg
(maximum 400 mg
per dose)
Every 12
hours
60 days
Plague
10 mg/kg
(maximum 400 mg
per dose)
Every 8 to
12 hours
10–21 days
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
•
Injection: 400 mg/200 mL
------------------------------ CONTRAINDICATIONS ----------------------------
•
Known hypersensitivity to CIPRO or other quinolones (4.1, 5.7)
•
Concomitant administration with tizanidine (4.2)
----------------------- WARNINGS AND PRECAUTIONS ---------------------
•
Hypersensitivity and other serious reactions: Serious and sometimes
fatal reactions (for example, anaphylactic reactions) may occur after first
or subsequent doses of CIPRO IV. Discontinue CIPRO IV at the first
sign of skin rash, jaundice or any sign of hypersensitivity. (4.1, 5.6, 5.7)
•
Hepatotoxicity: Discontinue immediately if signs and symptoms of
hepatitis occur. (5.8)
•
Clostridium difficile-Associated Diarrhea: Evaluate if colitis occurs.
(5.10)
•
QT Prolongation: Prolongation of the QT interval and isolated cases of
torsade de pointes have been reported. Avoid use in patients with known
prolongation, those with hypokalemia, and with other drugs that prolong
the QT interval. (5.11, 7, 8.5)
------------------------------ ADVERSE REACTIONS ----------------------------
The most common adverse reactions ≥1% were nausea, diarrhea, liver
function tests abnormal, vomiting, central nervous system disturbance, local
intravenous site reactions eosinophilia, headache, restlessness, and rash. (6)
TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT
BAYER HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1
800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS ----------------------------
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant
use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor
prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have
been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum
creatinine (7)
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
See full prescribing information for pediatric patients (8.4) and use in
geriatric (8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 7/2016
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING
TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY,
CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION
OF MYASTHENIA GRAVIS
1 INDICATIONS AND USAGE
1.1 Skin and Skin Structure Infections
1.2 Bone and Joint Infections
1.3 Complicated Intra-Abdominal Infections
1.4 Nosocomial Pneumonia
1.5 Empirical Therapy for Febrile Neutropenia Patients
1.6 Inhalational Anthrax (Post-Exposure)
1.7 Plague
1.8 Chronic Bacterial Prostatitis
1.9 Lower Respiratory Tract Infections
1.10 Urinary Tract Infections
1.11 Acute Sinusitis
1.12 Usage
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in Adults
2.2 Dosage in Pediatric Patients
2.3 Dosage Modifications in Patients with Renal Impairment
2.4 Preparation of CIPRO IV for Administration
2.5 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Hypersensitivity
4.2 Tizanidine
5 WARNINGS AND PRECAUTIONS
5.1 Disabling and Potentially Irreversible Serious Adverse Reactions
Including Tendinitis and Tendon Rupture, Peripheral Neuropathy,
and Central Nervous System Effects ‘
5.2 Tenditis and Tendon Rupture
5.3 Peripheral Neuropathy
5.4 Central Nervous System Effects
5.5 Exacerbation of Myasthenia Gravis
5.6 Other Serious and Sometimes Fatal Reactions
5.7 Hypersensitivity Reactions
5.8 Hepatotoxicity
5.9 Serious Adverse Reactions with Concomitant Theophylline
5.10 Clostridium difficile-Associated Diarrhea
5.11 Prolongation of the QT Interval
5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic
Effects in Animals
5.13 Photosensitivity/Phototoxicity
5.14 Development of Drug Resistant Bacteria
5.15 Potential Risks With Concomitant Use of Drugs Metabolized by
Cytochrome P450 1A2 Enzymes
5.17 Crystalluria
5.16 Periodic Assessment of Organ System Functions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Adverse Laboratory Changes
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in
Pediatric Patients
14.3 Inhalational Anthrax in Adults and Pediatrics
14.4 Plague
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
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FULL PRESCRIBING INFORMATION
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON
RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM
EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
• Fluoroquinolones, including CIPRO IV®, have been associated with disabling and
potentially irreversible serious adverse reactions that have occurred together [see
Warnings and Precautions (5.1)] including:
o Tendinitis and tendon rupture [see Warnings and Precautions (5.2)]
o Peripheral neuropathy [see Warnings and Precautions (5.3)]
o Central nervous system effects [see Warnings and Precautions (5.4)]
Discontinue CIPRO immediately and avoid the use of fluoroquinolones, including
CIPRO, in patients who experience any of these serious adverse reactions [see Warnings
and Precautions (5.1)].
• Fluoroquinolones, including CIPRO IV, may exacerbate muscle weakness in patients
with myasthenia gravis. Avoid CIPRO IV in patients with known history of
myasthenia gravis [see Warnings and Precautions (5.5)].
• Because fluoroquinolones, including CIPRO, have been associated with serious adverse
reactions [see Warnings and Precautions (5.1–5.15)], reserve CIPRO for use in patients
who have no alternative treatment options for the following indications:
o Acute exacerbation of chronic bronchitis [see Indications and Usage (1.9)]
o Acute Sinusitis [see Indications and Usage (1.11)]
1
INDICATIONS AND USAGE
1.1
Skin and Skin Structure Infections
CIPRO IV is indicated in adult patients for treatment of skin and skin structure infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin
susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus
pyogenes.
1.2
Bone and Joint Infections
CIPRO IV is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter
cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
1.3
Complicated Intra-Abdominal Infections
CIPRO IV is indicated in adult patients for treatment of complicated intra-abdominal infections (used in
combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus
mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
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1.4
Nosocomial Pneumonia
CIPRO IV is indicated in adult patients for treatment of nosocomial pneumonia caused by Haemophilus
influenzae or Klebsiella pneumoniae.
1.5 Empirical Therapy for Febrile Neutropenic Patients
CIPRO IV is indicated in adult patients for the treatment of febrile neutropenia in combination with
piperacillin sodium [see Clinical Studies (14.1)].
1.6 Inhalational Anthrax (Post-Exposure)
CIPRO IV is indicated in adults and pediatric patients from birth to 17 years of age for treatment of
inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure
to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely
to predict clinical benefit and provided the initial basis for approval of this indication.1 Supportive clinical
information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax
bioterror attacks of October 2001 [see Clinical Studies (14.3)].
1.7 Plague
CIPRO IV is indicated for treatment of plague, including pneumonic and septicemic plague, due to
Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17
years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for
feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see
Clinical Studies (14.4)].
1.8 Chronic Bacterial Prostatitis
CIPRO IV is indicated in adult patients for treatment of chronic bacterial prostatitis caused by
Escherichia coli or Proteus mirabilis.
1.9 Lower Respiratory Tract Infections
CIPRO IV is indicated in adult patients for treatment of lower respiratory tract infections caused by
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniaeCIPRO
IV is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to
Streptococcus pneumonia.
CIPRO IV is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by
Moraxella catarrhalis.
Because fluoroquinolones, including CIPRO IV, have been associated with serious adverse reactions [see
Warnings and Precautions (5.1-5.15)] and for some patients AECB is self-limiting, reserve CIPRO IV for
treatment of AECB in patients who have no alternative treatment options.
1.10 Urinary Tract Infections
Urinary Tract Infection in Adults
CIPRO IV is indicated in adult patients for treatment of urinary tract infections caused by Escherichia
coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia
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rettgeri, Morganella morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa,
methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus
faecalis.
Complicated Urinary Tract Infections and Pyelonephritis in Pediatric Patients
CIPRO IV is indicated in pediatric patients one to 17 years of age for treatment of complicated urinary
tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Use in Specific Populations (8.4)].
Although effective in clinical trials, CIPRO IV is not a drug of first choice in the pediatric population due
to an increased incidence of adverse reactions compared to controls, including reactions related to joints
and/or surrounding tissues. CIPRO IV, like other fluoroquinolones, is associated with arthropathy and
histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions
(5.12), Adverse Reactions (6.1), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].
1.11 Acute Sinusitis
CIPRO IV is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus
influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
Because fluoroquinolones, including CIPRO IV, have been associated with serious adverse reactions [see
Warnings and Precautions (5.1–5.15)] and for some patients acute sinusitis is self-limiting, reserve
CIPRO for treatment of acute sinusitis in patients who have no alternative treatment options.
1.12 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and
other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are
available, they should be considered in selecting or modifying antibacterial therapy. In the absence of
such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered. Appropriate culture and susceptibility tests should be performed before treatment in order
to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin.
Therapy with CIPRO IV may be initiated before results of these tests are known; once results become
available appropriate therapy should be continued.
As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
2 DOSAGE AND ADMINISTRATION
CIPRO IV should be administered intravenously at dosages described in the appropriate Dosage
Guidelines tables.
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2.1 Dosage in Adults
The determination of dosage and duration for any particular patient must take into consideration the
severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the
patient’s host-defense mechanisms, and the status of renal and hepatic function.
Table 1: Adult Dosage Guidelines
Infection1
Dose
Frequency
Usual Duration
Skin and Skin Structure
400 mg
every 8 to 12 hours
7–14 days
Bone and Joint
400 mg
every 8 to 12 hours
4 to 8 weeks
Complicated Intra
Abdominal2
400 mg
every 12 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
CIPRO IV
Empirical Therapy In
400 mg
every 8 hours
Febrile Neutropenic
and
7–14 days
Patients
Piperacillin
50 mg/kg
every 4 hours
Inhalational
Anthrax(Post-Exposure)3
400 mg
every 12 hours
60 days
Plague3
400 mg
every 8 to 12 hours
14 days
Chronic Bacterial
Prostatitis
400 mg
every 12 hours
28 days
Lower Respiratory Tract
Infections
400 mg
every 8 to 12 hours
7–14 days
Urinary Tract Infections
200 mg to 400 mg
every 8 to 12 hours
7–14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
1.
Due to the designated pathogens (see Indications and Usage.)
2.
Used in conjunction with metronidazole.
3.
Begin administration as soon as possible after suspected or confirmed exposure.
Conversion of Intravenous to Oral Dosing in Adults
Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension
when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology (12.3)].
Table 2: Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO IV Dosage
250 mg Tablet every 12 hours
200 mg intravenous every 12 hours
500 mg Tablet every 12 hours
400 mg intravenous every 12 hours
750 mg Tablet every 12 hours
400 mg intravenous every 8 hours
2.2 Dosage in Pediatric Patients
Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by
the severity of the infection.
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Table 3: Pediatric Dosage Guidelines
Infection
Dose
(mg/kg)
Frequency
Total Duration
Complicated Urinary Tract or
Pyelonephritis
(patients from 1 to 17 years of age)1
6 mg/kg to 10 mg/kg
(maximum 400 mg per dose; not to
be exceeded even in patients
weighing more than 51 kg)
Every 8 hours
10–21 days1
Inhalational Anthrax
(Post-Exposure)2
10 mg/kg
(maximum 400 mg per dose)
Every 12
hours
60 days
Plague2,3
10 mg/kg
(maximum 400 mg per dose)
Every 8 to 12
hours
10–21 days
1.
The total duration of therapy for cUTI and pyelonephritis in the clinical trial was determined by the physician. The mean
duration of treatment was 11 days (range 10 to 21 days).
2.
Begin drug administration as soon as possible after suspected or confirmed exposure.
3.
Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis.
2.3 Dosage Modifications in Patients with Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table
4.
Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal
Function
Creatinine Clearance (mL/min)
Dose
>30
See Usual Dosage.
5–29
200–400 mg every 18–24 hours
When only the serum creatinine concentration is known, the following formulas may be used to estimate
creatinine clearance:
Men - Creatinine clearance (mL/min) = Weight (kg) x (140 – age)
72 x serum creatinine (mg/dL)
Women - 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment and hepatic insufficiency, careful
monitoring is suggested.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric
patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m2).
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2.4 Preparation of CIPRO IV for Administration
Flexible Containers
CIPRO IV is available as a 0.2% premixed solution in 5% dextrose in flexible containers of 200 mL. The
solutions in flexible containers do not need to be diluted and may be infused as described above.
2.5 Important Administration Instructions
Intravenous Infusion
CIPRO IV should be administered by intravenous infusion over a period of 60 minutes. Slow infusion of
a dilute solution into a larger vein will minimize patient discomfort and reduce the risk of venous
irritation.
Hydration of Patients Receiving CIPRO IV
Adequate hydration of patients receiving CIPRO IV should be maintained to prevent the formation of
highly concentrated urine. Crystalluria has been reported with quinolones [see Warnings and Precautions
(5.16), Adverse Reactions (6.1), Nonclinical Toxicology (13.2) and Patient Counseling Information (17)].
3 DOSAGE FORMS AND STRENGTHS
Injection (200 mL in 5% Dextrose, 400 mg, 0.2%) Premix in Flexible Containers, for intravenous
infusion
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antibacterials, or any of the product components [see Warnings and
Precautions (5.7)].
4.2 Tizanidine
Concomitant administration with tizanidine is contraindicated [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1
Disabling and Potentially Irreversible Serious Adverse Reactions Including
Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous
System Effects
Fluoroquinolones, including CIPRO IV, have been associated with disabling and potentially irreversible
serious adverse reactions from different body systems that can occur together in the same patient.
Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral
neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe
headaches, and confusion). These reactions can occur within hours to weeks after starting CIPRO IV.
Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see
Warnings and Precautions (5.2, 5.3, 5.4)].
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Discontinue CIPRO IV immediately at the first signs or symptoms of any serious adverse reaction. In
addition, avoid the use of fluoroquinolones, including CIPRO IV, in patients who have experienced any
of these serious adverse reactions associated with fluoroquinolones.
5.2 Tendinitis and Tendon Rupture
Fluoroquinolones, including CIPRO IV, have been associated with an increased risk of tendinitis and
tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. This
adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator
cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can
occur, within hours or days of starting CIPRO IV, or as long as several months after completion of
fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.
The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients
over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung
transplants. Other factors, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and
tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk
factors. Discontinue CIPRO IV immediately if the patient experiences pain, swelling, inflammation or
rupture of a tendon. Avoid fluoroquinolones, including CIPRO IV, in patients who have a history of
tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions (6.2)].
5.3 Peripheral Neuropathy
Fluoroquinolones, including CIPRO IV, have been associated with an increased risk of peripheral
neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons
resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients
receiving fluoroquinolones, including CIPRO IV. Symptoms may occur soon after initiation of CIPRO IV
and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions
(6.1, 6.2)].
Discontinue CIPRO IV immediately if the patient experiences symptoms of peripheral neuropathy
including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including
light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to
minimize the development of an irreversible condition. Avoid fluoroquinolones, including CIPRO IV, in
patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6.1, 6.2).]
5.4 Central Nervous System Effects
Fluoroquinolones, including CIPRO IV, have been associated with an increased risk of central nervous
system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor
cerebri), and toxic psychosis CIPRO IV may also cause central nervous system (CNS) events including:
nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors,
hallucinations, depression, and, psychotic reactions have progressed to suicidal ideations/thoughts and
self-injurious behavior such as attempted or completed suicide. These reactions may occur following the
first dose. Advise patients receiving CIPRO IV to inform their healthcare provider immediately if these
reactions occur, discontinue the drug, and institute appropriate care. CIPRO IV, like other
fluoroquinolones, is known to trigger seizures or lower the seizure threshold. As with all
fluoroquinolones, use CIPRO IV with caution in epileptic patients and patients with known or suspected
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CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe
cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain
structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the
seizure threshold (for example, certain drug therapy, renal dysfunction). Use CIPRO IV when the benefits
of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS
side effects. Cases of status epilepticus have been reported. If seizures occur, discontinue CIPRO IV [see
Adverse Reactions (6.1) and Drug Interactions (7)].
5.5 Exacerbation of Myasthenia Gravis
Fluoroquinolones, including CIPRO IV, have neuromuscular blocking activity and may exacerbate
muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including
deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients
with myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis [see
Adverse Reactions (6.2)].
5.6 Other Serious and Sometimes Fatal Adverse Reactions
Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to
uncertain etiology, have been reported in patients receiving therapy with quinolones, including CIPRO
IV. These events may be severe and generally occur following the administration of multiple doses.
Clinical manifestations may include one or more of the following:
• Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-
Johnson syndrome);
• Vasculitis; arthralgia; myalgia; serum sickness;
• Allergic pneumonitis;
• Interstitial nephritis; acute renal insufficiency or failure;
• Hepatitis; jaundice; acute hepatic necrosis or failure;
• Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
Discontinue CIPRO IV immediately at the first appearance of a skin rash, jaundice, or any other sign of
hypersensitivity and supportive measures instituted [see Adverse Reactions (6.1, 6.2)].
5.7 Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose,
have been reported in patients receiving fluoroquinolone therapy, including CIPRO IV. Some reactions
were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial
edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other
resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids,
pressor amines, and airway management, including intubation, as indicated [see Adverse Reactions (6.1)].
5.8 Hepatotoxicity
Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal
events, have been reported with CIPRO IV. Acute liver injury is rapid in onset (range 1–39 days), and is
often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed.
Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms
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of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment
immediately.
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice,
especially in patients with previous liver damage, who are treated with CIPRO IV [see Adverse Reactions
(6.2, 6.3)].
5.9 Serious Adverse Reactions with Concomitant Theophylline
Serious and fatal reactions have been reported in patients receiving concurrent administration of
Intravenous CIPRO and theophylline. These reactions have included cardiac arrest, seizure, status
epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have
also occurred.
Although similar serious adverse reactions have been reported in patients receiving theophylline alone,
the possibility that these reactions may be potentiated by CIPRO cannot be eliminated. If concomitant use
cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Drug
Interactions (7)].
5.10 Clostridium difficile-Associated Diarrhea
Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including CIPRO IV, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.
difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients
who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD
has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial
treatment of C. difficile, and institute surgical evaluation as clinically indicated [see Adverse Reactions
(6.1)].
5.11 Prolongation of the QT Interval
Some fluoroquinolones, including CIPRO IV, have been associated with prolongation of the QT interval
on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during
postmarketing surveillance in patients receiving fluoroquinolones, including CIPRO IV. Avoid CIPRO IV
in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de
pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as
hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or
bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class
III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.
Elderly patients may also be more susceptible to drug-associated effects on the QT interval [see Adverse
Reactions (6.2) and Use in Specific Populations (8.5)].
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5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
CIPRO IV is indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of
inhalational anthrax (post exposure), and plague [see Indications and Usage (1.10, 1.6, 1.7)]. An
increased incidence of adverse reactions compared to controls, including reactions related to joints and/or
surrounding tissues, has been observed [see Adverse Reactions (6.1)].
In pre-clinical studies, oral administration of CIPRO IV caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species[see Use in Specific Populations
(8.4) and Nonclinical Toxicology (13.2)].
5.13 Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as
exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema)
involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the
forearms, dorsa of the hands), can be associated with the use of quinolones, including CIPRO IV, after
sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue
CIPRO IV if phototoxicity occurs[sSee Adverse Reactions (6.1).]
5.14 Development of Drug Resistant Bacteria
Prescribing CIPRO IV in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
5.15 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2
Enzymes
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of CIPRO IV
and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine,
tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co-
administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-
administered drug [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
5.16 Crystalluria
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in
the urine of laboratory animals, which is usually alkaline [see Nonclinical Toxicology (13.2)]. Crystalluria
related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic.
Avoid alkalinity of the urine in patients receiving CIPRO IV. Hydrate patients well to prevent the
formation of highly concentrated urine [see Dosage and Administration (2.4)].
5.17 Periodic Assessment of Organ System Functions
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
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6 ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in
other sections of labeling:
• Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions
(5.1)]
• Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)]
• Peripheral Neuropathy [see Warnings and Precautions (5.3)]
• Central Nervous System Effects [see Warnings and Precautions (5.4)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.5)]
• Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions (5.9)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.10)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.11)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.12)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adult Patients
During clinical investigations with oral and parenteral CIPRO IV, 49,038 patients received courses of the
drug.
The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
In clinical trials the following adverse reactions were reported in greater than 1% of patients treated with
intravenous CIPRO IV: nausea, diarrhea, central nervous system disturbance, local intravenous site
reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Local intravenous
site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin
reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is
not contraindicated unless the reactions recur or worsen.
Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin
Patients
System Organ Class
Adverse Reactions
Body as a Whole
Abdominal Pain/Discomfort
Pain
Cardiovascular
Cardiopulmonary Arrest
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System Organ Class
Adverse Reactions
Myocardial Infarction
Tachycardia
Syncope
Hypertension
Angina Pectoris
Vasodilation
Central Nervous System
Restlessness
Seizures (including Status Epilepticus)
Paranoia
Psychosis (toxic)
Depression (potentially culminating in self-injurious behavior,
such as suicidal ideations/thoughts and attempted or completed
suicide)
Phobia
Depersonalization
Manic Reaction
Unresponsiveness
Ataxia
Hallucinations
Dizziness
Paresthesia
Tremor
Insomnia
Nightmares
Irritability
Malaise
Abnormal Gait
Migraine
Gastrointestinal
Ileus
Gastrointestinal Bleeding
Pancreatitis
Hepatic Necrosis
Intestinal Perforation
Dyspepsia
Constipation
Oral Ulceration
Mouth Dryness
Anorexia
Flatulence
Hepatitis
Hemic/Lymphatic
Agranulocytosis
Prolongation of Prothrombin Time
Petechia
Metabolic/Nutritional
Hyperglycemia
Hypoglycemia
Musculoskeletal
Arthralgia
Joint Stiffness
Muscle Weakness
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System Organ Class
Adverse Reactions
Renal/Urogenital
Renal Failure
Interstitial Nephritis
Hemorrhagic Cystitis
Renal Calculi
Frequent Urination
Gynecomastia
Crystalluria
Cylindruria
Hematuria
Albuminuria
Respiratory
Respiratory Arrest
Dyspnea
Laryngeal Edema
Hemoptysis
Bronchospasm
Skin/Hypersensitivity
Allergic Reactions
Anaphylactic Reactions including life-threatening anaphylactic
shock
Erythema Multiforme/Stevens-Johnson Syndrome
Exfoliative Dermatitis
Toxic Epidermal Necrolysis
Vasculitis
Angioedema
Extremities
Purpura
Fever
Pruritus
Urticaria
Increased Perspiration
Erythema Nodosum
Thrombophlebitis
Burning
Photosensitivity/Phototoxicity Reaction
Special Senses
Decreased Visual Acuity
Blurred Vision
Disturbed Vision (diplopia, chromatopsia, and photopsia)
Anosmia
Hearing Loss
Tinnitus
Nystagmus
Bad Taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing CIPRO (Intravenous and
Intravenous/Oral. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction
profile of CIPRO was comparable to that of the control drugs.
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Pediatric Patients
Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous
ciprofloxacin was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric
patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration
of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A
total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6
weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal
adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually
within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution
of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse
reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse
reactions was consistently higher in the ciprofloxacin group compared to the control group across all age
subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period
was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated
patients (Table 6).
Table 6: Musculoskeletal Adverse Reactions1 as Assessed by the IPSC
CIPRO
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval2
(-0.8%, +7.2%)
Age Group
12 months to 24 months
1/36 (2.8%)
0/41
2 years to <6 years
5/124 (4%)
3/118 (2.5%)
6 years to <12 years
18/143 (12.6%)
12/153 (7.8%)
12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval2
(-0.6%, + 9.1%)
1.
Included: arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain,
myalgia, arm pain, and decreased range of motion in a joint (knee, elbow, ankle, hip, wrist, and shoulder)
2.
The study was designed to demonstrate that the arthropathy rate for the CIPRO group did not exceed that of the control
group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could
not be concluded that the ciprofloxacin group had findings comparable to the control group.
The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness,
nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were
41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most
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frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9%
(31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin
treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse
reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator
patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%,
vomiting 4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash
1.8%.
Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for
the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5–17 years). Sixty seven
patients received CIPRO IV 10 mg/kg/dose every 8 hours for one week followed by CIPRO tablets 20
mg/kg/dose every 12 hours to complete 10–21 days treatment and 62 patients received the combination of
ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8
hours for a total of 10–21 days. Periodic musculoskeletal assessments were conducted by treatment-
blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0–
93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin
group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects
in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the
patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were
similar in nature and frequency between treatment arms. The efficacy of CIPRO for the treatment of acute
pulmonary exacerbations in pediatric cystic fibrosis patients has not been established.
In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected
that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur
in pediatric patients.
6.2 Postmarketing Experience
The following adverse reactions have been reported from worldwide marketing experience with
fluoroquinolones, including CIPRO IV. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure (Table 7).
Table 7: Postmarketing Reports of Adverse Drug Reactions
System Organ Class
Adverse Reactions
Cardiovascular
QT prolongation
Torsade de Pointes
Vasculitis and ventricular arrhythmia
Central Nervous System
Hypertonia
Myasthenia
Exacerbation of myasthenia gravis
Peripheral neuropathy
Polyneuropathy
Twitching
Gastrointestinal
Pseudomembranous colitis
Hemic/Lymphatic
Pancytopenia (life threatening or fatal outcome)
Methemoglobinemia
Hepatobiliary
Hepatic failure (including fatal cases)
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Infections and Infestations
Candidiasis (oral, gastrointestinal, vaginal)
Investigations
Prothrombin time prolongation or decrease
Cholesterol elevation (serum)
Potassium elevation (serum)
Musculoskeletal
Myalgia
Myoclonus
Tendinitis
Tendon rupture
Psychiatric Disorders
Agitation
Confusion
Delirium
Skin/Hypersensitivity
Acute generalize exanthematous pustulosis
(AGEP)
Fixed eruption
Serum sickness-like reaction
Special Senses
Anosmia
Hyperesthesia
Hypesthesia
Nystagmus
Taste loss
6.3 Adverse Laboratory Changes
Changes in laboratory parameters while on CIPRO IV therapy are listed below:
• Hepatic-Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin
• Hematologic-Elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
• Renal-Elevations of serum creatinine, BUN, and uric acid
• Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring were: decreased leukocyte count, elevated atypical lymphocyte count, immature
WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT), decreased
BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum
potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring during
administration of ciprofloxacin were: elevation of serum amylase, decrease of blood glucose,
pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased
prothrombin time, hemolytic anemia, and bleeding diathesis.
7 DRUG INTERACTIONS
Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-
administration of CIPRO IV with other drugs primarily metabolized by CYP1A2 results in increased
plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-
administered drug.
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Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and CIPRO IV
is contraindicated due to the potentiation of hypotensive
and sedative effects of tizanidine [see Contraindications
(4.2)]
Theophylline
Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of CIPRO IV with
theophylline may result in increased risk of a patient
developing central nervous system (CNS) or other
adverse reactions. If concomitant use cannot be avoided,
monitor serum levels of theophylline and adjust dosage
as appropriate [eee Warnings and Precautions (5.9)].
Drugs Known to
Prolong QT Interval
Avoid Use
CIPRO IV may further prolong the QT interval in
patients receiving drugs known to prolong the QT
interval (for example, class IA or III antiarrhythmics,
tricyclic antidepressants, macrolides, antipsychotics)
[see Warnings and Precautions (5.11) and Use in
Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution
Glucose-lowering effect
potentiated
Hypoglycemia sometimes severe has been reported
when CIPRO IV and oral antidiabetic agents, mainly
sulfonylureas (for example, glyburide, glimepiride),
were co-administered, presumably by intensifying the
action of the oral antidiabetic agent. Fatalities have been
reported. Monitor blood glucose when ciprofloxacin is
co-administered with oral antidiabetic drugs [see
Adverse Reactions (6.1)].
Phenytoin
Use with caution
Altered serum levels of
phenytoin (increased and
decreased)
To avoid the loss of seizure control associated with
decreased phenytoin levels and to prevent phenytoin
overdose-related adverse reactions upon CIPRO IV
discontinuation in patients receiving both agents,
monitor phenytoin therapy, including phenytoin serum
concentration during and shortly after co-administration
of CIPRO IV with phenytoin.
Cyclosporine
Use with caution
(transient elevations in serum
creatinine)
Monitor renal function (in particular serum creatinine)
when ciprofloxacin is co-administered with
cyclosporine.
Anti-coagulant drugs
Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and
general status of the patient so that the contribution of
CIPRO IV to the increase in INR (international
normalized ratio) is difficult to assess. Monitor
prothrombin time and INR frequently during and shortly
after co-administration of CIPRO IV with an oral anti
coagulant (for example, warfarin).
Methotrexate
Use with caution
Inhibition of methotrexate renal
tubular transport potentially
leading to increased
Potential increase in the risk of methotrexate associated
toxic reactions. Therefore, carefully monitor patients
under methotrexate therapy when concomitant CIPRO
IV therapy is indicated.
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Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
methotrexate plasma levels
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and
appropriate dose adjustment of ropinirole is
recommended during and shortly after co-administration
with CIPRO IV [see Warnings and Precautions (5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse
reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with
CIPRO IV are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl
salicylic acid) in combination of very high doses of
quinolones have been shown to provoke convulsions in
pre-clinical studies and in postmarketing.
Sildenafil
Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical
Pharmacology (12.3)].
Duloxetine
Avoid Use
Five-fold increase in duloxetine
exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in
elevated levels and prolongation
of serum half-life
CIPRO IV inhibits the formation of paraxanthine after
caffeine administration (or pentoxifylline containing
products). Monitor for xanthine toxicity and adjust dose
as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid
Use with caution
(interferes with renal tubular
secretion of CIPRO and
increases CIPRO serum levels)
Potentiation of CIPRO IV toxicity may occur.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. CIPRO IV should not be used
during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An
expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the
Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a
substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that
there is no risk.2
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3 In utero exposure to
fluoroquinolones during embryogenesis was not associated with increased risk of major malformations.
The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6%
for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous
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abortions, prematurity and low birth weight did not differ between the groups and there were no clinically
significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).4 There were 70 ciprofloxacin exposures, all within the first trimester. The
malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were
both within background incidence ranges. No specific patterns of congenital abnormalities were found.
The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.2, 3 However, these small postmarketing epidemiology studies,
of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk
for less common defects or to permit reliable and definitive conclusions regarding the safety of
ciprofloxacin in pregnant women and their developing fetuses.
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3
times the maximum daily human dose based upon body surface area, respectively) and have revealed no
evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100
mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body
surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or
teratogenicity was observed.
8.3 Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is
unknown. Because of the potential risk of serious adverse reactions (including articular damage) in
infants nursing from mothers taking CIPRO IV, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Although effective in clinical trials, CIPRO IV is not a drug of first choice in the pediatric population due
to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO IV,
cause arthropathy in juvenile animals [see Warnings and Precautions (5.12) and Nonclinical Toxicology
(13.2)].
Complicated Urinary Tract Infection and Pyelonephritis
CIPRO IV is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric
patients 1 to 17 years of age. Although effective in clinical trials, CIPRO IV is not a drug of first choice in
the pediatric population due to an increased incidence of adverse reactions compared to the controls,
including events related to joints and/or surrounding tissues [see Adverse Reactions (6.1) and Clinical
Studies (14.2)].
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Inhalational Anthrax (Post-Exposure)
CIPRO IV is indicated in pediatric patients from birth to 17 years of age for inhalational anthrax (post
exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients
is appropriate [see Dosage and Administration (2.2) and Clinical Studies (14.3)].
Plague
CIPRO IV is indicated in pediatric patients from birth to 17 years of age, for treatment of plague,
including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague.
Efficacy studies of CIPRO IV could not be conducted in humans with pneumonic plague for feasibility
reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The
risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate [see
Indications and Usage (1.7), Dosage and Administration (2.2), and Clinical Studies (14.4)].
8.5 Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture
when being treated with a fluoroquinolone such as CIPRO IV. This risk is further increased in patients
receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand,
shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to
several months after fluoroquinolone treatment have been reported. Caution should be used when
prescribing CIPRO IV to elderly patients especially those on corticosteroids. Patients should be informed
of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider
if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning, Warnings and Precautions
(5.2), and Adverse Reactions (6.2)].
In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over
3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and
10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but greater sensitivity of
some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with
normal renal function. However, since some older individuals experience reduced renal function by virtue
of their advanced age, care should be taken in dose selection for elderly patients, and renal function
monitoring may be useful in these patients [see Dosage and Administration (2.3) and Clinical
Pharmacology (12.3)].
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO IV with concomitant drugs that can result in
prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk
factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see
Warnings and Precautions (5.11)].
8.6 Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the intestine. These alternative
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pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal
impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with
severe renal dysfunction [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients
with acute hepatic insufficiency, have not been studied.
10 OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Observe the
patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and
acidify, if required, to prevent crystalluria. Adequate hydration must be maintained. Only a small amount
of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 mg/kg and 300 mg/kg.
11 DESCRIPTION
CIPRO IV (ciprofloxacin) is a synthetic antimicrobial agent for intravenous (IV) administration.
Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3
quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions
are available as sterile 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. CIPRO IV
contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is not made with natural rubber latex. Solutions in contact with the plastic container
can leach out certain of its chemical components in very small amounts within the expiration period, for
example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has
been confirmed in tests in animals according to USP biological tests for plastic containers as well as by
tissue culture toxicity studies.
The glucose content for the 200 mL flexible container is 10 g.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].
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12.3 Pharmacokinetics
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg CIPRO IV to normal volunteers, the
mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively (Table 9).
Table 9: Steady-state Ciprofloxacin Serum Concentrations (mcg/mL)
After 60-minute INTRAVENOUS Infusions every 12 hours.
Time after starting the infusion
Dose
30 minutes
1 hour
3 hour
6 hour
8 hour
12 hour
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose
on an every 12 hour regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by
first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12
hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to
that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state
equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg intravenous dose
results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given
every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours
(Table 10).
Table 10: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous
Doses
Parameters
500 mg
400 mg
750 mg
400 mg
every 12 hours
every 12 hours,
every 12 hours,
every 8 hours,
AUC (mcg•hr/mL)
orally.
13.71
intravenously
12.71
orally
31.62
intravenously
32.93
Cmax (mcg/mL)
2.97
4.56
3.59
4.07
1.
AUC 0-12h
2.
AUC 24h = AUC 0-12h x 2
3.
AUC 24h = AUC 0-8h x 3
Distribution
After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue
concentrations often exceed serum concentrations in both men and women, particularly in genital tissue
including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions,
mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into
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the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism
After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose. The metabolites have
antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human
cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other
drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and
could lead to clinically significant adverse events of the co-administered drug [see Contraindications
(4.2), Warnings and Precautions (5.9, 5.15) and Drug Interactions (7)].
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg intravenous dose, concentrations in the urine usually exceed 200
mcg/mL 0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing.
Following a 400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after
dosing and are usually greater than 30 mcg/mL 8–12 hours after dosing. The renal clearance is
approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after
dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (<less than1%) is recovered from the
bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5
days after dosing.
Specific Populations
Elderly
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older
than 65 years) as compared to young adults. Although the Cmax is increased 16% to 40%, the increase in
mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in
the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant [see Use in Specific Populations (8.5)].
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage
adjustments may be required [see Use in Specific Populations (8.6) and Dosage and Administration
(2.3)].
Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute
hepatic insufficiency, have not been fully studied.
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Pediatrics
Following a single oral dose of 10 mg/kg CIPRO suspension to 16 children ranging in age from 4 months
to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2
mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*hr/mL). There was no apparent age-dependence, and no
notable increase in Cmax or AUC upon multiple dosing (10 mg/kg three times a day). In children with
severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax
was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2
mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The
AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32.0 mcg*hr/mL) and 16.5 mcg*hr/mL
(range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective age groups. These values are within the
range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is approximately 4 hours–5 hours,
and the bioavailability of the oral suspension is approximately 60%.
Drug-Drug Interactions
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly
increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500 mg twice
a day for 3 days). Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the
potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Ropinirole
In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once
daily with 500 mg CIPRO twice-daily, the mean Cmax and mean AUC of ropinirole were increased by
60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose
adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see
Warnings and Precautions (5.15)].
Clozapine
Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum
concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively.
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine
dosage during and shortly after co-administration with CIPRO IV are advised.
Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to
healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold.
Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in
the exposure of sildenafil upon co-administration of CIPRO IV.
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Duloxetine
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the
CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold
increase in mean Cmax of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg
ciprofloxacin twice daily resulted in an increase of lidocaine Cmax and AUC by 12% and 26%,
respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible
interaction with CIPRO IV and an increase in adverse reactions related to lidocaine may occur upon
concomitant administration.
12.4 Microbiology
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA
replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones
occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or
drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to
ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6
.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro
and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Bacillus anthracis
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative bacteria
Citrobacter koseri
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Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Yersinia pestis
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of
the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to
the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in
treating clinical infections due to these bacteria has not been established in adequate and well-controlled
clinical trials.
Gram-positive bacteria
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
Gram-negative bacteria
Acinetobacter lwoffi
Aeromonas hydrophila
Edwardsiella tarda
Enterobacter aerogenes
Klebsiella oxytoca
Legionella pneumophila
Pasteurella multocida
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility
test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports
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that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports
should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).
These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs
should be determined using a standardized test method (broth and/or agar).5, 6, 7 The MIC values should be
interpreted according to criteria provided in Table 11.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the
susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a
standardized test method.6, 7, 8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to
test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in
Table 11.
Table 11: Susceptibility Test Interpretive Criteria for Ciprofloxacin
MIC (mcg/mL)
Zone Diameter (mm)
Bacteria
S
I
R
S
I
R
Enterobacteriaceae
≤1
2
≥4
≥21
16–20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus aureus
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus epidermidis
≤1
2
≥4
≥21
16–20
≤15
Staphylococcus saprophyticus
≤1
2
≥4
≥21
16–20
≤15
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16–20
≤15
Haemophilus influenzae1
≤1
-
-
≥21
-
-
Haemophilus parainfluenzae1
≤1
-
-
≥21
-
-
Streptococcus pneumoniae
≤1
2
≥4
≥21
16–20
≤15
Streptococcus pyogenes
≤1
2
≥4
≥21
16–20
≤15
Bacillus anthracis1
≤0.25
-
-
-
-
-
Yersinia pestis1
≤0.25
-
-
-
-
-
S=Susceptible, I=Intermediate, and R=Resistant.
1.
The current absence of data on resistant isolates precludes defining any results other than “Susceptible”. If isolates yield
MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the
antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of
the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if
the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be
repeated. This category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be used. This category also
provides a buffer zone that prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to
inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
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Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy
and precision of supplies and reagents used in the assay, and the techniques of the individuals performing
the test.5, 6, 7, 8 Standard ciprofloxacin powder should provide the following range of MIC values noted in
Table 12. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 12 should be
achieved.
Table 12: Acceptable Quality Control Ranges for Ciprofloxacin
Bacteria
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03
34–42
Pseudomonas aeruginosa ATCC 27853
0.25–1
25–33
Staphylococcus aureus ATCC 29213
0.12–0.5
-
Staphylococcus aureus ATCC 25923
-
22–30
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A total of 8 in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are
listed below:
• Salmonella/Microsome Test (Negative)
• E. coli DNA Repair Assay (Negative)
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V79 Cell HGPRT Test (Negative)
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerevisiae Point Mutation Assay (Negative)
• Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte DNA Repair Assay (Positive)
• Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative
results:
• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due
to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively
(approximately 1.7- times and 2.5- times the highest recommended therapeutic dose based upon body
surface area, respectively).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice
treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
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recommended human dose based upon body surface area), as opposed to 34 weeks when animals were
treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks
in mice treated concomitantly with UVA and other quinolones.9
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no
data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times
the highest recommended therapeutic dose based upon body surface area) revealed no evidence of
impairment.
13.2 Animal Toxicology and/or Pharmacology
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested [see Warnings and Precautions (5.11)].
Damage of weight-bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30
mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral
ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- times and 3.5-times the
pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes
which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg
(approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints
were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free
period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did
not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with
ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses
as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon body
surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were
noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release, since they
are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection
also produces hypotension but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and
indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals
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14 CLINICAL STUDIES
14.1 Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of CIPRO IV, 400 mg intravenously every 8 hours, in combination with
piperacillin sodium, 50 mg/kg intravenously every 4 hours, for the empirical therapy of febrile
neutropenic patients were studied in one large pivotal multicenter, randomized trial and were compared to
those of tobramycin, 2 mg/kg intravenously every 8 hours, in combination with piperacillin sodium, 50
mg/kg intravenously every 4 hours.
Clinical response rates observed in this study were as follows:
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 13.
Table 13: Clinical Response Rates
Outcomes
CIPRO IV/Piperacillin
N = 233
Tobramycin/Piperacillin
N = 237
Success (%)
Success (%)
Clinical Resolution of Initial
Febrile Episode with No
Modifications of Empirical
Regimen1
63 (27%)
52 (21.9%)
Clinical Resolution of Initial
Febrile Episode Including
Patients with Modifications of
Empirical Regimen
187 (80.3%)
185 (78.1%)
Overall Survival
224 (96.1%)
223 (94.1%)
1.
To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological eradication of
infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of infection; and (4) no
modification of empirical antibiotic regimen
14.2 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in Pediatric
Patients
Ciprofloxacin, administered IV and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
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The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 14.
Table 14: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days Post-
Treatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at
5 to 9 Days Post-Treatment1
84.4% (178/211)
78.3% (181/231)
95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days Post-
Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
1.
Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were
5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.
14.3 Inhalational Anthrax in Adults and Pediatrics
Additional information
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in
survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been
evaluated in various human populations. The mean peak serum concentration achieved at steady-state in
human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400
mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these
regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak
plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26
mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After
the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on
cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin
serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication.11
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5
x 105) spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration
(MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied,
mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral
dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough
concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL.10 Mortality due to
anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-
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exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.11
More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were
also given anthrax vaccine or were switched to alternative antibacterial drugs. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
14.4 Plague
A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110
LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean
peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49
mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day
6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day
6 and Day 10) were < 0.5 mcg/mL. Animals were randomized to receive either a 10-day regimen of
intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body
temperature greater than 1.5oC over baseline for two hours), or at 76 hours post-challenge, whichever
occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the
placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one
ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure
of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all
timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of
low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was
negative.12
15 REFERENCES
1. 21 CFR 314.510 (Subpart H–Accelerated Approval of New Drugs for Life-Threatening Illnesses).
2. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6):1336-1339.
4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS).
Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
5. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–9th Edition. CLSI
Document M7-A9 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite
2500, Wayne, PA, 19087-1898.
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing; 24th Informational Supplement. CLSI Document M100 S24 [2014]. Clinical
and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–2nd
Edition. CLSI Document M45-A2 [2010]. Clinical and Laboratory Standards Institute, 950 West
Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
8. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk
Susceptibility Tests; Approved Standard–11th Edition. CLSI Document M2-A11[2012]. Clinical and
Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.
9. CReport presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory
Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER,
Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852,
USA.
10. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
11. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167:1239-42.
12. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for
treatment of Pneumonic Plague.
16 HOW SUPPLIED/STORAGE AND HANDLING
CIPRO IV (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution in flexible
containers not made with natural rubber latex.
SIZE
STRENGTH
NDC NUMBER
200 mL
5% Dextrose 400 mg, 0.2%
50419-759-01
STORAGE
Store between 5–25ºC (41–77ºF).
Protect from light, avoid excessive heat, protect from freezing.
Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500 mg and CIPRO
(ciprofloxacin*) 5% and 10% Oral Suspension.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Serious Adverse Reactions
Advise patients to stop taking CIPRO if they experience an adverse reaction and to call their healthcare
provider for advice on completing the full course of treatment with another antibacterial drug.
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Inform patients of the following serious adverse reactions that have been associated with CIPRO IV or
other fluoroquinolone use:
• Disabling and potentially irreversible serious adverse reactions that may occur together: Inform
patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and
tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated
with use of CIPRO IV and may occur together in the same patient. Inform patients to stop taking
CIPRO immediately if they experience an adverse reaction and to call their healthcare provider.
• Tendon Disorders: Instruct patients to contact their healthcare provider if they experience pain,
swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and
refrain from exercise; and discontinue CIPRO treatment. Symptoms may be irreversible. The risk of
severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age,
in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with
ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If
symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, immediately discontinue CIPRO and tell them to contact their physician.
• Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased
intracranial pressure): Inform patients that convulsions have been reported in patients receiving
fluoroquinolones, including CIPRO IV. Instruct patients to notify their physician before taking this
drug if they have a history of convulsions. Inform patients that they should know how they react to
CIPRO before they operate an automobile or machinery or engage in other activities requiring mental
alertness and coordination. Instruct patients to notify their physician if persistent headache with or
without blurred vision occurs.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of
myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of
muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions,
even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other
skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting
angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or
other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events)
has been reported in patients taking CIPRO IV. Instruct patients to inform their physician if they
experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever,
weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light
colored bowel movements or dark colored urine.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop
watery and bloody stools (with or without stomach cramps and fever) even as late as two or more
months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact
their physician as soon as possible.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or
family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or
recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III
Reference ID: 3963446
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(amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any
symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of
consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician
if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric
patients to notify their child’s physician of any joint-related problems that occur during or following
ciprofloxacin therapy [see Warnings and Precautions (5.12) and Use in Specific Populations (8.4)].
• Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. CIPRO
increases the effects of tizanidine (Zanaflex®).
• Theophylline: Inform patients that CIPRO IV may increase the effects of theophylline. Life-
threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical
help if they experience seizures, palpitations, or difficulty breathing.
• Caffeine: Inform patients that CIPRO IV may increase the effects of caffeine. There is a possibility
of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported
in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or
artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be
outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun
exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or
skin eruption occurs, instruct patients to contact their physician.
Antibacterial Resistance
Inform patients that antibacterial drugs including CIPRO IV should only be used to treat bacterial
infections. They do not treat viral infections (for example, the common cold). When CIPRO IV prescribed
to treat a bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing
the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable by CIPRO IV or other
antibacterial drugs in the future.
Administration
Inform patients to drink fluids liberally while taking CIPRO to avoid formation of highly concentrated
urine and crystal formation in the urine.
Drug Interactions Oral Antidiabetic Agents
Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were
co-administered; if low blood sugar occurs with CIPRO IV, instruct them toconsult their physician and
that their antibacterial medicine may need to be changed.
Anthrax and Plague Studies
Inform patients given CIPRO IV for this condition that efficacy studies could not be conducted in humans
for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies
conducted in animals.
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride)
for oral suspension
CIPRO® XR (Sip-row)
(ciprofloxacin hydrochloride)
Tablets
for oral use
CIPRO® IV (Sip-row)
(ciprofloxacin)
Injection
for intravenous infusion
Read this Medication Guide before you start taking CIPRO and each time you get a
refill. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about CIPRO?
CIPRO, a fluoroquinolone antibacterial medicine, can cause serious side
effects. Some of these serious side effects can happen at the same time
and could result in death.
If you get any of the following serious side effects while you take CIPRO, you
should stop taking CIPRO immediately and get medical help right away.
1. Tendon rupture or swelling of the tendon (tendinitis).
•
Tendon problems can happen in people of all ages who take CIPRO.
Tendons are tough cords of tissue that connect muscles to bones.
Symptoms of tendon problems may include:
o pain
o swelling
o tears and swelling of the tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
• The risk of getting tendon problems while you take CIPRO is higher if
you:
o are over 60 years of age
o are taking steroids (corticosteroids)
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
o have had a kidney, heart or lung transplant
•
Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO.
• Other reasons that can increase your risk of tendon problems can include:
o physical activity or exercise
o kidney failure
o tendon problems in the past, such as in people with rheumatoid arthritis
(RA)
• Stop taking CIPRO immediately and get medical help right away at
the first sign of tendon pain, swelling or inflammation.
The most common area of pain and swelling is the Achilles tendon at the
back of your ankle. This can also happen with other tendons.
• Tendon rupture can happen while you are taking or after you have
finished taking CIPRO. Tendon ruptures can happen within hours or days
of taking CIPRO and have happened up to several months after people have
finished taking their fluoroquinolone.
• Stop taking CIPRO immediately and get medical help right away if
you get any of the following signs or symptoms of a tendon rupture:
o hear or feel a snap or pop in a tendon area
o bruising right after an injury in a tendon area
o unable to move the affected area or bear weight
2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to
the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones,
including CIPRO. Stop taking CIPRO immediately and talk to your healthcare provider right
away if you get any of the following symptoms of peripheral neuropathy in your arms, hands,
legs, or feet:
• pain
• numbness
• burning
• weakness
• tingling
CIPRO may need to be stopped to prevent permanent nerve damage.
3. Central Nervous System (CNS) effects. Seizures have been reported in people who take
fluoroquinolone antibacterial medicines, including CIPRO. Tell your healthcare provider if you
have a history of seizures before you start taking CIPRO. CNS side effects may happen as
soon as after taking the first dose of CIPRO. Stop taking CIPRO immediately and talk to your
healthcare provider right away if you get any of these side effects, or other changes in mood
or behavior:
o seizures
o trouble sleeping
o hear voices, see things, or sense things
o nightmares
that are not there (hallucinations)
o feel lightheaded or dizzy
o feel restless
o feel more suspicious (paranoia)
o tremors
o suicidal thoughts or acts
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
o feel anxious or nervous
o headaches that will not go away, with or
o confusion
without blurred vision
o depression
4. Worsening of myasthenia gravis (a problem that causes muscle
weakness). Fluoroquinolones like CIPRO may cause worsening of myasthenia
gravis symptoms, including muscle weakness and breathing problems. Tell your
healthcare provider if you have a history of myasthenia gravis before you start
taking CIPRO. Call your healthcare provider right away if you have any
worsening muscle weakness or breathing problems.
What is CIPRO?
CIPRO is a fluoroquinolone antibacterial medicine used in adults age 18 years and
older to treat certain infections caused by certain germs called bacteria. These
bacterial infections include:
• urinary tract infection
• chronic prostate infection
• lower respiratory tract infection
• sinus infection
• skin infection
• bone and joint infection
• nosocomial pneumonia
• intra-abdominal infection, complicated
• infectious diarrhea
• typhoid (enteric) fever
• cervical and urethral gonorrhea, uncomplicated
• people with a low white blood cell count and a fever
• inhalational anthrax
• plague
• Studies of CIPRO for use in the treatment of plague and anthrax were done in
animals only, because plague and anthrax could not be studied in people.
• CIPRO should not be used in patients with acute exacerbation of chronic
bronchitis, acute uncomplicated cystitis, and sinus infections, if there are other
treatment options available.
• CIPRO should not be used as the first choice of antibacterial medicine to treat
lower respiratory tract infections cause by a certain type of bacterial called
Streptococcus pneumoniae.
• CIPRO is also used in children younger than 18 years of age to treat
complicated urinary tract and kidney infections or who may have breathed in
anthrax germs, have plague or have been exposed to plague germs.
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Children younger than 18 years of age have a higher chance of getting bone,
joint, or tendon (musculoskeletal) problems such as pain or swelling while taking
CIPRO. CIPRO should not be used as the first choice of antibacterial medicine in
children under 18 years of age.
• CIPRO XR is only used in adults 18 years of age and older to treat urinary
tract infections (complicated and uncomplicated), including kidney infections
(pyelonephritis).
• It is not known if CIPRO XR is safe and effective in children under 18 years of
age.
Who should not take CIPRO?
Do not take CIPRO if you:
• Have ever had a severe allergic reaction to an antibacterial medicine known as a
fluoroquinolone, or are allergic to ciprofloxacin hydrochloride or any of the
ingredients in CIPRO. See the end of this Medication Guide for a complete list of
ingredients in CIPRO.
•
Also take a medicine called tizanidine (Zanaflex®).
Ask your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking CIPRO?
Before you take CIPRO, tell your healthcare provider if you:
• have tendon problems; CIPRO should not be used in patients who have a history
of tendon problems
• have a disease that causes muscle weakness (myasthenia gravis); CIPRO should
not be used in patients who have a known history of myasthenia gravis
• have liver problems
• have central nervous system problems (such as epilepsy)
• have nerve problems; CIPRO should not be used in patients who have a history
of a nerve problem called peripheral neuropathy
• have or anyone in your family has an irregular heartbeat, especially a condition
called “QT prolongation”
• have or have had seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do
not work well.
• have joint problems including rheumatoid arthritis (RA)
• have trouble swallowing pills
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if CIPRO will harm
your unborn baby.
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• are breastfeeding or plan to breastfeed. CIPRO passes into breast milk. You and
your healthcare provider should decide whether you will take CIPRO or
breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
CIPRO and other medicines can affect each other causing side effects.
Especially tell your healthcare provider if you take:
• a steroid medicine
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• theophylline (such as Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• a medicine to control your heart rate or rhythm (antiarrhythmics)
• an oral anti-diabetes medicine
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®,
Extended Phenytoin Sodium®, Prompt Phenytoin Sodium®, Phenytek®)
• cyclosporine (Gengraf®, Neoral®, Sandimmune®, Sangcya®).
• a blood thinner (such as warfarin, Coumadin®, Jantoven®)
• methotrexate (Trexall®)
• ropinirole (Requip®)
• clozapine (Clozaril®, Fazaclo® ODT®)
• a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many common medicines for
pain relief are NSAIDs. Taking an NSAID while you take CIPRO or other
fluoroquinolones may increase your risk of central nervous system effects and
seizures.
• sildenafil (Viagra®, Revatio®)
• duloxetine
• products that contain caffeine
• probenecid (Probalan®, Col-probenecid ®)
• certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from
working correctly. Take CIPRO Tablets and Oral Suspension either 2 hours
before or 6 hours after taking these medicines, vitamins, or supplements:
o an antacid, multivitamin, or other medicine or supplements that has
magnesium, calcium, aluminum, iron, or zinc
o sucralfate (Carafate®)
o didanosine (Videx®, Videx EC®)
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Ask your healthcare provider for a list of these medicines if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
How should I take CIPRO?
• Take CIPRO exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much CIPRO to take and when to take
it.
• Take CIPRO Tablets in the morning and evening at about the same time each
day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your
healthcare provider if you cannot swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time
each day. Shake the CIPRO Oral Suspension bottle well each time before use for
about 15 seconds to make sure the suspension is mixed well. Close the bottle
completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare
provider if you cannot swallow the tablet whole.
• CIPRO IV is given to you by intravenous (IV) infusion into your vein, slowly,
over 60 minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-
fortified juices alone, but may be taken with a meal that contains these
products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses of CIPRO, or stop taking it, even if you begin to feel
better, until you finish your prescribed treatment unless:
o you have tendon problems. See “What is the most important
information I should know about CIPRO?”
o you have nerve problems. See “What is the most important
information I should know about CIPRO?”
o you have central nervous system problems. See “What is the most
important information I should know about CIPRO?”
o you have a serious allergic reaction. See “What are the possible side
effects of CIPRO?”
o your healthcare provider tells you to stop taking CIPRO
Taking all of your CIPRO doses will help make sure that all of the bacteria are
killed. Taking all of your CIPRO doses will help lower the chance that the
bacteria will become resistant to CIPRO. If you become resistant to CIPRO,
CIPRO and other antibacterial medicines may not work for you in the future.
Reference ID: 3963446
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you take too much CIPRO, call your healthcare provider or get medical help
right away.
What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate
machinery, or do other activities that require mental alertness or coordination
until you know how CIPRO affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can
make your skin sensitive to the sun (photosensitivity) and the light from
sunlamps and tanning beds. You could get a severe sunburn, blisters or swelling
of your skin. If you get any of these symptoms while you take CIPRO, call your
healthcare provider right away. You should use a sunscreen and wear a hat and
clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
CIPRO may cause serious side effects, including:
• See, “What is the most important information I should know about
CIPRO?”
• Serious allergic reactions. Serious allergic reactions, including death, can
happen in people taking fluoroquinolones, including CIPRO, even after only 1
dose. Stop taking CIPRO and get emergency medical help right away if you get
any of the following symptoms of a severe allergic reaction:
o hives
o trouble breathing or swallowing
o swelling of the lips, tongue, face
o throat tightness, hoarseness
o rapid heartbeat
o faint
o skin rash
Skin rash may happen in people taking CIPRO even after only 1 dose. Stop
taking CIPRO at the first sign of a skin rash and call your healthcare provider.
Skin rash may be a sign of a more serious reaction to CIPRO.
• Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who
take CIPRO. Call your healthcare provider right away if you have unexplained
symptoms such as:
o nausea or vomiting
o stomach pain
o fever
o weakness
o abdominal pain or tenderness
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o itching
o unusual tiredness
o loss of appetite
o light colored bowel movements
o dark colored urine
o yellowing of your skin or the whites of your eyes
Stop taking CIPRO and tell your healthcare provider right away if you have
yellowing of your skin or white part of your eyes, or if you have dark urine. These
can be signs of a serious reaction to CIPRO (a liver problem). Intestine infection
(Pseudomembranous colitis). Pseudomembranous colitis can happen with many
antibacterial medicines, including CIPRO. Call your healthcare provider right away if
you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may
have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or
more months after you have finished your antibacterial medicine.
• Serious heart rhythm changes (QT prolongation and torsade de
pointes). Tell your healthcare provider right away if you have a change in your
heart beat (a fast or irregular heartbeat), or if you faint. CIPRO may cause a
rare heart problem known as prolongation of the QT interval. This condition can
cause an abnormal heartbeat and can be very dangerous. The chances of this
event are higher in people:
o who are elderly
o with a family history of prolonged QT interval
o with low blood potassium (hypokalemia)
o who take certain medicines to control heart rhythm (antiarrhythmics)
• Joint Problems. Increased chance of problems with joints and tissues around
joints in children under 18 years old can happen. Tell your child’s healthcare
provider if your child has any joint problems during or after treatment with
CIPRO.
• Sensitivity to sunlight (photosensitivity). See “What should I avoid
while taking CIPRO?”
The most common side effects of CIPRO include:
• nausea
• diarrhea
• changes in liver function tests
• vomiting
• rash
Tell your healthcare provider about any side effect that bothers you, or that does
not go away.
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all the possible side effects of CIPRO. For more information, ask your
healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store CIPRO?
CIPRO Tablets
• Store at room temperature between 20° to 25°C (68° to 77°F).
CIPRO Oral Suspension
• Store microcapsules and diluent below 25°C (77°F).
• Do not freeze.
• After your CIPRO treatment is finished, safely throw away any unused oral
suspension.
CIPRO XR
• Store CIPRO XR between 59°F to 86°F (15°C to 30°C).
Keep CIPRO and all medicines out of the reach of children.
General Information about the safe and effective use of CIPRO.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use CIPRO for a condition for which it is not prescribed.
Do not give CIPRO to other people, even if they have the same symptoms that you
have. It may harm them.
This Medication Guide summarizes the most important information about CIPRO. If
you would like more information about CIPRO, talk with your healthcare provider.
You can ask your healthcare provider or pharmacist for information about CIPRO
that is written for healthcare professionals.
For more information call 1-888-842-2937.
What are the ingredients in CIPRO?
CIPRO Tablets:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide,
crospovidone, magnesium stearate, hypromellose, titanium dioxide, and
polyethylene glycol
CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients:
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o Microcapsules contains: povidone, methacrylic acid copolymer,
hypromellose, magnesium stearate, and Polysorbate 20
o Diluent contains: medium-chain triglycerides, sucrose, soy-lecithin,
water, and strawberry flavor
CIPRO XR:
• Active ingredient: ciprofloxacin hydrochloride
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate,
polyethylene glycol, silica colloidal anhydrous, succinic acid, and titanium
dioxide
CIPRO IV:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid
for pH adjustment
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
©2016 Bayer HealthCare Pharmaceuticals Inc.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Manufactured in Italy
CIPRO (ciprofloxacin HCl) Tablets Manufactured in Germany
This Medication Guide has been approved by the U.S. Food and Drug Administration
Revised: 7/2016
Reference ID: 3963446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:11.739198
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High Purity lndium
Chloride In-11 1
Sterile Solution
Diagnostic - For Use in Radiolabeling
OncoScint@, ProstaScint’“, and Zevalin”
(see package insert for indications)
For single dose, single use only
ProductCodes:INS.lPA/INS.lPAF
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICLORm
High Purity lndium Chloride In-111 Sterile Solution
Diagnostic-For
use in Radiolabeling
OncoScint,
ProstaScint, and Zevalin
For single dose, single use only
DESCRIPTION
INDICLOR lndium
In-ill
Chloride
is a diagnostic
radiopharmaceutical intended for radiolabeling OncoScint
(satumomab pendetide) or ProstaScint (capromab pendetide)
used for in viva diagnostic imaging procedures and for
radiolabeling Zevalin (ibrftumomab tiuxetan) in preparations
used for radioimmunotherapy procedures. It is supplied as a
sterile, pyrogen-free solution of lndium (Vr) Chloride in 0.04M
HCI. Each milliliter is supplied at a radioactive concentration of
370 MBq, 10 mCl of lndlum In-111 Chloride at time of calibration
(no carrier added, with specific activity of > 1.85 GBqlpg Iridium,
> 50 mCffmg lndium at time of calibration). The pH of the
solution is about 1.4.
RADIONUCLIDIC PURITY
A Cadmium Cd-l 12 enriched target is bombarded in a cyclotron
to produce lndium In-111 by the (p,2n) reaction. The
bombardment conditions, the energy of the proton beam and
the length of the bombardment are chosen to ensure an lndium
In-111 yield of high radionuclidic purity. Radionuclidic purity is
checked at release particularly for the presence of fndium
In-114. The relative proportion of this impurity increases, after
release of the batch, as a result of its longer half-life.
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Because of its beta-emitting
component
and its potentially
high
organ
dose
contribution,
lndium
In-114m
is particularly
important
if present above carefully
controlled
levels.
Release specifications:
c 0.08%
lndium In-114m
at calibration
time
< 0.16%
lndium In-114m
at expiration
time
RADIOCHEMICALPURITY
Release specification:
Not less than 95% lndium present as ionic
IrP.
Decay Platforln-111
and In-114&n-114
100,
In-114mh114
conlaminanllevol0.001
on calibration
day
1
0.1 -
,
0.01 -
0.001
-
0.0001I
I
I
I
I
I
I
I
I
I
I
I
J
-12
-10
-6
.6
-4
-2
0
2
4
6
0
10
12
Time(dayt)
-0. In-111
+ In-114mflrk114
mm Iwo. talnnuon day
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PHYSICAL CHARACTERISTICS
lndium
In-l 11 decays by electron
capture with a physical half-
life of 67.2 hours (2.8 days). The energies of the photons that are
useful for detection and imaging studies are listed in Table 1.
Table 1. Principal Radiation Emission Data’
Mean%/
Mean Energy
Radiation
Disintegration
WV
Gamma 2
90.2
171.3
Gamma 3
94
245.4
‘Kocher, David C., “Radioactive Decay Data Tables.” DOE/TIC-11026,115
(1961).
EXTERNAL RADIATION
The exposure
rate constant for 37 MBq, 1 mCi lndium In-l 11 is
8.3 x IO4 Clkglhr,
3.21
R/hr
at 1 cm. The first
half value
thickness of lead (Pb) for lndium
In-l 11 is 0.023 cm. A range of
values for the relative attenuation
of the radiation
emitted by this
radionuclide
that
results
from
the
interposition
of various
thicknesses
of Pb is shown in Table 2. For example, the use of
0.834 cm of lead will decrease the external
radiation exposure
by
a factor of about 1,000.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Iridium-111 Radiation Attenuation
of Lead ShieldinV
Shield Thickness
Coefficient
of
(Pb) cm
Attenuation
0.023
0.5
0.203
10’
0.513
1@2
0.834
I@’
1.12
IO’
‘Data
supplied
by
Oak
Ridge
Associated
Universities,
Radiopharmaceutical Internal Dose Information Center, 1984.
These estimates of attenuation
do not take into consideration
the
presence
of longer-lived
contaminants
with
higher
energy
protons,
namely tndium
In-l 14m/ll4.
To allow correction
for physical
decay of lndium
In-Ill,
the
fractions
that remain at selected intervals
before and after the
time of calibration
are shown in Table 3.
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. lndium In-111 Physical Decay Chart,
Half-Life 67.2 Hours (2.6 days)
Fraction
Fraction
_. Hours
Remaining
Hours
Remaining
.-
-48
-42
-36
-30
-24
-18
-12
-6
0’
1;
*Calibration Trme
1.64
1.54
1.44
1.36
1.28
1.20
1.13
1.06
1.00
0.94
0.88
0.83
0.78
0.74
0.69
0.65
0.61
0.58
0.54
0.51
0.48
CLINICAL
PHARMACOLOGY
Please refer to the package insert for OncoScint,
ProstaScint
or
Zevalin for this information
on the final drug product.
INDICATIONS
AND USAGE
INDICLOR
lndium
In-l 11 Chloride is indicated for radiolabeling
of monoclonal
antibodies
in preparations
used for
in viva
diagnostic
imaging
procedures.
lndiclor
is also indicated
for
radiolabeling
Zevalin
in
preparations
used
for
radioimmunotherapy
procedures.
Please refer to the package
insert
for monoclonal
antibody
preparations
for
information
regarding
the radiolabeled
product.
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Please refer to the package insert for OncoScint, ProstaScint or
Zevaiin for this information on the final drug product.
WARNINGS
The contents of the vial of INDICLOR lndium In-111 Chloride
solution are intended only to be used as an ingredient for
radiolabeling OncoScint or ProstaScint used for in viva
diagnostic imaging procedures and for radiolabeling Zevalin in
preparations used for radioimmunotherapy procedures.
lndiclor is not lo be administered directly to humans.
PRECAUTIONS
General:, Strict aseptic techniques should be used to maintain
sterility throughout the procedures for using this product.
Do not use after the expiration time and date stated on the label.
The contents of the vial are radioactive. Adequate shielding
must be maintained at all times.
CARCINOGENESIS,
MUTAGENESIS,
IMPAIRMENT
OF
FERTILITY
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
PREGNANCYCATEGORY
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
.
NURSING MOTHERS
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
PEDIATRIC USE
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
ADVERSE REACTIONS
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
DOSAGE AND ADMINISTRATION
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
RADIATION DOSIMETRY
Please refer to the package insert for OncoScint, ProstaScint or
Zevalin for this information on the final drug product.
STERILITY AND APYROGENICITY
This product is terminally sterilized by autoclave. A pyrogenicity
is confirmed before release by a Limulus test.
HOW SUPPLIED
INDICLOR Iridium-ill
Chloride is supplied in 1 mL vials
containing 0.2 milliliters, 74 MBq, 2.0 mCi or 0.5 milliliters, 185
MBq, 5.0 mCi of lndium In-ill
at calibration time. This
packaging design has been carefully selected to minimize
leaching of cationic and anionic impurities into the product
during transport and storage.
a
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SPECIAL HANDLING
AND STORAGE
Store at room temperature (15~25”C, 59-77°F).
This radiopharmaceutical is licensed by Illinois Depart-
ment of Nuclear Safety for distribution to persons licensed
pursuant to 32 III. Adm. Code 330.260(a) and Part 335,
Subpart E, 335.4010, or under equivalent licenses of an
Agreement State or a Licensing State.
It is recommended that the vial be kept inside its transpor-
tation shield whenever possible and that it be handled with
forceps when doses are being removed.
INS.1 PA - Wednesday Calibration
INS.1 PAF - Saturday Calibration
OncoScinte is a registered trademark of Cytogen Corporation.
ProstaScint- is a trademark of Cytogen Corporation.
Zevalin” is a trademark of IOEC Pharmaceutical Corporation.
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Amersham
Health
Medi-Physics,
inc.
Arlington
Heights,
IL 60004
Customer
Service:
l-800-292-8514
Professional
Services:
l-800-654-0118
Printed in U.S.A.
278851 D
Revised December
2001
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:11.762241
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/in111med021902LB.pdf', 'application_number': 19862, 'submission_type': 'SUPPL ', 'submission_number': 6}
|
11,799
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
BETAPACE®/BETAPACE AF safely and effectively. See full prescribing
information for BETAPACE/BETAPACE AF.
BETAPACE (sotalol hydrochloride) tablets, for oral use
Initial U.S. Approval: 1992
BETAPACE AF (sotalol hydrochloride) tablets, for oral use
Initial U.S. Approval: 1992
WARNING: LIFE THREATENING PROARRHYTHMIA
See full prescribing information for complete boxed warning.
•
Betapace/Betapace AF can cause life threatening ventricular
tachycardia associated with QT interval prolongation.
•
If the QT interval prolongs to 500 msec or greater, reduce the
dose, lengthen the dosing interval, or discontinue the drug.
•
Initiate or reinitiate in a facility that can provide cardiac
resuscitation and continuous electrocardiographic monitoring.
•
Adjust the dosing interval based on creatinine clearance.
--------------------------- INDICATIONS AND USAGE --------------------------
Betapace/Betapace AF is an antiarrhythmic indicated for:
•
the treatment of life threatening ventricular arrhythmias (1.1)
•
the maintenance of normal sinus rhythm in patients with atrial
fibrillation or flutter (AFIB/AFL) (1.2)
Limitations of Use
•
Avoid use in patients with asymptomatic ventricular premature
contraction (1.1)
•
Avoid use in patients with minimally symptomatic or easily reversible
AFIB/AFL (1.2)
---------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Betapace/Betapace AF: Initial dosage in adults is 80 mg twice daily.
Increase the dose as needed in increments of 80 mg/day, every 3 days to
a maximum 320 mg total daily dose (2.2)
•
Pediatrics: Dosage depends on age (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
80 mg,120 mg and 160 mg tablets (3)
------------------------------ CONTRAINDICATIONS ----------------------------
For the treatment of AFIB/AFL or ventricular arrythmias
•
Sinus bradycardia, 2nd or 3rd degree AV block, sick sinus syndrome (4)
•
Congenital or acquired long QT syndrome, (4)
•
Serum potassium <4 mEq/L(4)
•
Cardiogenic shock, decompensated heart failure (4)
•
Bronchial asthma or related bronchospastic conditions (4)
•
Hypersensitivity to sotalol (4)
For the treatment of AFIB/AFL also contraindicated for:
•
QT interval >450 ms (4)
•
Creatine clearance <40 ml/min (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------------
•
QT prolongation, bradycardia, AV block, hypotension, worsening heart
failure: Reduce dose or discontinue (5.1)
•
Acute exacerbation of coronary artery disease upon cessation of therapy:
Do not abruptly discontinue (5.5)
•
Correct any electrolyte disturbances (5.1)
•
May mask symptoms of hypoglycemia or worsen hyperglycemia in
diabetic patients; monitor (5.7)
------------------------------ ADVERSE REACTIONS ----------------------------
The most common adverse reactions (≥2%) for Betapace are: fatigue 4%,
bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia
2%, and dizziness 2%. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma
at 1-866-488-4423 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS ----------------------------
•
Class I or III Antiarrhythmics or other drugs that prolong the QT
interval: Avoid concomitant use (7.1)
•
Digoxin, calcium channel blocker: increased risk of bradycardia,
hypotension, heart failure (7.2)
•
Dosage of insulin or antidiabetic drugs may need adjustment (7.5)
•
Aluminum or magnesium-based antacids reduce sotalol exposure (7.7)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 05/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING PROARRHYTHMIA
1 INDICATIONS AND USAGE
1.1 Life-Threatening Ventricular Arrhythmias
1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter (AFIB/AFL)
2 DOSAGE AND ADMINISTRATION
2.1 General Safety Measures for Initiation of Oral Sotalol Therapy
2.2 Adult Dose for Ventricular Arrhythmias
2.3 Adult Dose for Prevention of Recurrence of AFIB/AFL
2.4 Pediatric Dose for Ventricular Arrhythmias or AFIB/AFL
2.5 Dosage for Patients with Renal Impairment
2.6 Preparation of Extemporaneous Oral Solution
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 QT Prolongation and Proarrhythmia
5.2 Bradycardia/Heart Block/Sick Sinus Syndrome
5.3 Hypotension
5.4 Heart Failure
5.5 Cardiac Ischemia after Abrupt Discontinuation
5.6 Bronchospasm
5.7 Masked Signs of Hypoglycemia in Diabetics
5.8 Thyroid Abnormalities
5.9 Anaphylaxis
5.10 Major Surgery
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Antiarrhythmics and other QT Prolonging Drugs
7.2 Digoxin
7.3 Calcium-Channel Blocking Drugs
7.4 Catecholamine-Depleting Agents
7.5 Insulin and Oral Antidiabetics
7.6 Clonidine
7.7 Antacids
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Ventricular Arrhythmias
14.2 Clinical Studies in Supra-ventricular Arrhytmias
14.3 Clinical Studies in Patients with Myocardial Infarction
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
Reference ID: 3929060
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING PROARRHYTHMIA
To minimize the risk of drug-induced arrhythmia, initiate or reinitiate oral sotalol in a facility that can
provide cardiac resuscitation and continuous electrocardiographic monitoring.
Sotalol can cause life threatening ventricular tachycardia associated with QT interval prolongation.
If the QT interval prolongs to 500 msec or greater, reduce the dose, lengthen the dosing interval, or
discontinue the drug.
Calculate creatinine clearance to determine appropriate dosing [see Dosage and Administration (2.5)].
1 INDICATIONS AND USAGE
1.1 Life-Threatening Ventricular Arrhythmias
Betapace/Betapace AF is indicated for the treatment of life-threatening, documented ventricular arrhythmias,
such as sustained ventricular tachycardia (VT).
Limitation of Use:
Betapace/Betapace AF may not enhance survival in patients with ventricular arrhythmias. Because of the
proarrhythmic effects of Betapace/Betapace AF, including a 1.5 to 2% rate of Torsade de Pointes (TdP) or new
ventricular tachycardia/fibrillation (VT/VF) in patients with either non-sustained ventricular tachycardia
(NSVT) or supraventricular arrhythmias (SVT), its use in patients with less severe arrhythmias, even if the
patients are symptomatic, is generally not recommended. Avoid treatment of patients with asymptomatic
ventricular premature contractions [see Warnings and Precautions (5.2).]
1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter (AFIB/AFL)
Betapace/Betapace AF is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of
AFIB/AFL) in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.
Limitation of Use:
Because Betapace/Betapace AF can cause life-threatening ventricular arrhythmias, reserve its use for patients in
whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB that is easily reversed (by Valsalva
maneuver, for example) should usually not be given Betapace/Betapace AF.
2 DOSAGE AND ADMINISTRATION
2.1 General Safety Measures for Initiation of Oral Sotalol Therapy
Withdraw other antiarrhythmic therapy before starting Betapace/Betapace AF and monitor carefully for a
minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits [see Drug Interactions (7)].
Hospitalize patients initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are
achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.
Initiate oral sotalol therapy in the presence of personnel trained in the management of serious arrhythmias.
Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and
Reference ID: 3929060
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magnesium levels before initiating therapy. Measure serum creatinine and calculate an estimated creatinine
clearance in order to establish the appropriate dosing interval (insert cross ref to renal dosing). Continually
monitor patients with each uptitration in dose, until they reach steady state. Determine QTc 2 to 4 hours after
every dose.
Discharge patients on sotalol therapy from an in-patient setting with an adequate supply of sotalol to allow
uninterrupted therapy until the patient can fill a sotalol prescription.
Advise patients who miss a dose to take the next dose at the usual time. Do not double the dose or shorten the
dosing interval.
2.2 Adult Dose for Ventricular Arrhythmias
The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day
every 3 days provided the QTc <500 msec [see Warnings and Precautions (5.1)]. Continually monitor patients
until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily
dose of 160 to 320 mg/day, given in two or three divided doses (because of the long terminal elimination half-
life of sotalol, dosing more than a two times a day is usually not necessary). Oral doses as high as 480-640
mg/day have been utilized in patients with refractory life-threatening arrhythmias.
2.3 Adult Dose for Prevention of Recurrence of AFIB/AFL
The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day
every 3 days provided the QTc <500 msec [see Warnings and Precautions (5.1)]. Continually monitor patients
until steady state blood levels are achieved. Most patients will have satisfactory response with 120 mg twice
daily. Initiation of sotalol in patients with creatinine clearance < 40 ml/min or QTc >450 is contraindicated [see
Contraindication (4)].
2.4 Pediatric Dose for Ventricular Arrhythmias or AFIB/AFL
Use the same precautionary measures for children as you would use for adults when initiating and re-initiating
sotalol treatment.
For children aged about 2 years and older
For children aged about 2 years and older, with normal renal function, doses normalized for body surface area
are appropriate for both initial and incremental dosing. Since the Class III potency in children is not very
different from that in adults, reaching plasma concentrations that occur within the adult dose range is an
appropriate guide [see Clinical Pharmacology (12.1, 12.3)].
From pediatric pharmacokinetic data the following is recommended:
For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent
to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (approximately
equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical
response, heart rate and QTc, with increased dosing being preferably carried out in-hospital. At least 36 hours
should be allowed between dose increments to attain steady-state plasma concentrations of sotalol in patients
with age-adjusted normal renal function.
For children aged about 2 years or younger
For children aged about 2 years or younger, the above pediatric dosage should be reduced by a factor that
depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in months.
Reference ID: 3929060
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graph
For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater
should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97)=29.1 mg/m2, administered
three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting
dose would be (30 X 0.68)=20 mg/m2, administered three times daily. For a child aged about 1 week, the initial
starting dose should be multiplied by 0.3; the starting dose would be (30 X 0.3)=9 mg/m2. Use similar
calculations for dose titration.
Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also
increase. Thus, in neonates the time to steady-state may be as long as a week or longer.
2.5 Dosage for Patients with Renal Impairment
Adults
Use of sotalol in any age group with decreased renal function should be at lower doses or increased intervals
between doses. It will take much longer to reach steady-state with any dose and/or frequency of administration.
Closely monitor heart rate and QTc.
Dose escalations in renal impairment should be done after administration of at least 5 doses at appropriate
intervals (Table 1). Sotalol is partly removed by dialysis; specific advice is unavailable on dosing patients on
dialysis.
The initial dose of 80 mg and subsequent doses should be administered at the intervals listed in Table 1 or Table
2.
Reference ID: 3929060
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Table 1: Dosing Intervals for treatment of Ventricular Arrhythmias in renal impairment
Creatinine Clearance mL/min
Dosing Interval (hours)
> 60
12
30–59
24
10–29
36–48
< 10
Dose should be individualized
Table 2: Dosing Intervals for treatment of AFIB/AFL in renal impairment
Creatinine Clearance mL/min
Dosing Interval (hours)
> 60
12
40–59
24
<40
Contraindicated
2.6 Preparation of Extemporaneous Oral Solution
Betapace/Betapace AF Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium
benzoate (Syrup, NF) as follows:
1. Measure 120 mL of Simple Syrup.
2. Transfer the syrup to a 6-ounce amber plastic (polyethylene terephthalate [PET]) prescription bottle. An
oversized bottle is used to allow for a headspace, so that there will be more effective mixing during shaking
of the bottle.
3. Add five (5) Betapace/Betapace AF 120 mg tablets to the bottle. These tablets are added intact; it is not
necessary to crush the tablets. The addition of the tablets can also be done first. The tablets can also be
crushed if preferred. If the tablets are crushed, care should be taken to transfer the entire quantity of tablet
powder into the bottle containing the syrup.
4. Shake the bottle to wet the entire surface of the tablets. If the tablets have been crushed, shake the bottle
until the endpoint is achieved.
5. Allow the tablets to hydrate for at least two hours.
6. After at least two hours have elapsed, shake the bottle intermittently over the course of at least another two
hours until the tablets are completely disintegrated. The tablets can be allowed to hydrate overnight to
simplify the disintegration process.
The endpoint is achieved when a dispersion of fine particles in the syrup is obtained.
This compounding procedure results in a solution containing 5 mg/mL of sotalol HCl. The fine solid particles
are the water-insoluble inactive ingredients of the tablets.
Stability studies indicate that the suspension is stable for three months when stored at 15°C to 30°C (59°F to
86°F) [see USP Controlled Room Temperature] and ambient humidity.
3 DOSAGE FORMS AND STRENGTHS
Betapace is supplied as capsule-shaped, light-blue, scored tablets:
• 80 mg imprinted with “BETAPACE” on one side and 80 mg on the other
Reference ID: 3929060
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• 120 mg imprinted with “BETAPACE” on one side and 120 mg on the other
• 160 mg imprinted with “BETAPACE” on one side and 160 mg on the other
Betapace AF is supplied as capsule-shaped, white scored tablet:
• 80 mg imprinted with “BHCP” on one side and 80 mg on the other
• 120 mg imprinted with “BHCP” on one side and 120 mg on the other
• 160 mg imprinted with “BHCP” on one side and 160 mg on the other
4 CONTRAINDICATIONS
Betapace/Betapace AF is contraindicated in patients with:
• Sinus bradycardia, sick sinus syndrome, second and third degree AV block, unless a functioning pacemaker
is present
• Congenital or acquired long QT syndromes
• Cardiogenic shock or decompensated heart failure
• Serum potassium <4 mEq/L
• Bronchial asthma or related bronchospastic conditions
• Hypersensitivity to sotalol
For the treatment of AFIB/AFL, Betapace/Betapace AF is also contraindicated in patients with:
• Baseline QT interval >450 ms
• Creatinine clearance < 40 mL/min
5 WARNINGS AND PRECAUTIONS
5.1 QT Prolongation and Proarrhythmia
Betapace/Betapace AF can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF,
primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia
associated with QT interval prolongation. Factors such as reduced creatinine clearance, female sex, higher
doses, reduced heart rate and history of sustained VT/VF or heart failure increase the risk of TdP. The risk of
TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the
ECG for excessive increases in the QT interval [see Dosage and Administration (2.1)].
Correct hypokalemia or hypomagnesemia prior to initiating Betapace/Betapace AF, as these conditions can
exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention
should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or
patients receiving concomitant diuretic drugs.
Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment
[see Dosage and Administration (2.1)].
In general, do not use sotalol with other drugs known to cause QT prolongation [see Drug Interactions (7.1)].
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5.2 Bradycardia/Heart Block/Sick Sinus Syndrome
Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials,
and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes.
Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or
3rd-degree AV block is approximately 1%.
Betapace/Betapace AF is contraindicated in patients with sick sinus syndrome because it may cause sinus bradycardia,
sinus pauses or sinus arrest.
5.3 Hypotension
Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in
hypotension. Monitor hemodynamics in patients with marginal cardiac compensation.
5.4 Heart Failure
New onset or worsening heart failure may occur during initiation or uptitration of sotalol because of its beta-
blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur.
5.5 Cardiac Ischemia after Abrupt Discontinuation
Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and
myocardial infarction may occur. When discontinuing chronically administered Betapace/Betapace AF,
particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks, if
possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat
appropriately (consider use of an alternative beta blocker). Warn patients not to interrupt therapy without their
physician’s advice. Because coronary artery disease may be common, but unrecognized, in patients treated with
sotalol, abrupt discontinuation may unmask latent coronary insufficiency.
5.6 Bronchospasm
Patients with bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta-
blockers. If Betapace/Betapace AF is to be administered, use the smallest effective dose, to minimize inhibition
of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors.
5.7 Masked Signs of Hypoglycemia in Diabetics
Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness
and sweating may not be significantly affected. Elevated blood glucose levels and increased insulin
requirements can occur in diabetic patients.
5.8 Thyroid Abnormalities
Avoid abrupt withdrawal of beta-blockade in patients with thyroid disease because it may lead to an
exacerbation of symptoms of hyperthyroidism, including thyroid storm. Beta-blockade may mask certain
clinical signs (for example, tachycardia) of hyperthyroidism.
5.9 Anaphylaxis
While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a
more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be
unresponsive to the usual doses of epinephrine used to treat the allergic reaction.
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5.10 Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery;
however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of
general anesthesia and surgical procedures.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and
Class III (cardiac action potential duration prolongation) effects and are dose related.
Ventricular Arrhythmias
Serious Adverse Reactions
In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral
sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular
arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT was about 0.7%. Incidence
of Torsade de Pointes arrhythmias in patients with VT/VF are shown in Table 3 below.
Table 3: Percent Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With
Sustained VT/VF
Daily Dose (mg)
Torsade de Pointes
Incidence
Mean QTc * (msec)
80
0 (69)
463 (17)
160
0.5 (832)
467 (181)
320
1.6 (835)
473 (344)
480
4.4 (459)
483 (234)
640
3.7 (324)
490 (185)
>640
5.8 (103)
512 (62)
( ) Number of patients assessed
*highest on-therapy value
Table 4 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline in
patients with ventricular arrhythmias. It should be noted, however, that the highest on-therapy QTc was in many
cases the one obtained at the time of the Torsade de Pointes event, so that the table overstates the predictive
value of a high QTc.
Table 4: Relationship Between QTc Interval Prolongation and Torsade de Pointes
On-Therapy
Incidence of
Change from
Incidence of
QTc Interval
Torsade de Pointes Baseline in QTc
Torsade de Pointes
(msec)
(msec)
<500
1.3% (1787)
<65
1.6% (1516)
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500-525
3.4% (236)
65-80
3.2% (158)
525-550
5.6% (125)
80-100
4.1% (146)
>550
10.8% (157)
100-130
5.2% (115)
>130
7.1% (99)
( ) Number of patients assessed
Table 5: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo group and less frequent
than in the Betapace groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with
Ventricular Ectopy
Body System/
Adverse Reaction (Preferred
Term)
Placebo
Betapace Total Daily Dose
N = 37
(%)
320 mg
N = 38
(%)
640 mg
N = 39
(%)
CARDIOVASCULAR
Chest Pain
5.4
7.9
15.4
Dyspnea
2.7
18.4
20.5
Palpitation
2.7
7.9
5.1
Vasodilation
2.7
0.0
5.1
NERVOUS SYSTEM
Asthenia
8.1
10.5
20.5
Dizziness
5.4
13.2
17.9
Fatigue
10.8
26.3
25.6
Headache
5.4
5.3
7.7
Lightheaded
8.1
15.8
5.1
Sleep Problem
2.7
2.6
7.7
RESPIRATORY
Upper Respiratory Tract
Problem
2.7
2.6
12.8
SPECIAL SENSES
Visual Problem
2.7
5.3
0.0
The most common adverse reactions leading to discontinuation of Betapace in trials of patients with ventricular
arrhythmias are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%,
and dizziness 2%. Incidence of discontinuation for these adverse reactions was dose related.
One case of peripheral neuropathy that resolved on discontinuation of Betapace and recurred when the patient
was rechallenged with the drug was reported in an early dose tolerance study.
Pediatric Patients
In an unblinded multicenter trial of 25 pediatric patients with SVT and/or VT receiving daily doses of
30, 90 and 210 mg/m2 with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious
new arrhythmias were observed. One (1) patient, receiving 30 mg/m2 daily, was discontinued because of
increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and
210 mg/m2 daily dose levels. They included QT prolongation (2 patients), sinus pauses/bradycardia (1 patient),
increased severity of atrial flutter and reported chest pain (1 patient). Values for QTc ≥ 525 msec were seen in
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2 patients at the 210 mg/m2 daily dose level. Serious adverse events including death, Torsade de Pointes, other
proarrhythmias, high-degree A-V blocks, and bradycardia have been reported in infants and/or children.
Atrial Fibrillation/Atrial Flutter
Placebo-controlled Clinical Trials
In a pooled clinical trial population consisting of 4 placebo-controlled studies with 275 patients with atrial
fibrillation (AFIB)/atrial flutter (AFL) treated with 160 to 320 mg doses of Betapace AF, the following adverse
reactions presented in Table 6 occurred in at least 2% of placebo-treated patients and at a lesser rate than
Betapace-treated patients. The data are presented by incidence of reactions in the Betapace AF and placebo
groups by body system and daily dose.
Table 6: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo group and less frequent
than in the Betapace AF groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL
Body System/
Adverse Reaction (Preferred Term)
Placebo
Betapace AF Total Daily Dose
N = 282
(%)
160-240 mg
N = 153
(%)
> 240-320 mg
N = 122
(%)
CARDIOVASCULAR
Bradycardia
2.5
13.1
12.3
GASTROINTESTINAL
Diarrhea
2.1
5.2
5.7
Nausea/Vomiting
5.3
7.8
5.7
Pain abdomen
2.5
3.9
2.5
GENERAL
Fatigue
8.5
19.6
18.9
Hyperhidrosis
3.2
5.2
4.9
Weakness
3.2
5.2
4.9
MUSCULOSKELETAL/CONNECTIVE TISSUE
Pain musculoskeletal
2.8
2.6
4.1
NERVOUS SYSTEM
Dizziness
12.4
16.3
13.1
Headache
5.3
3.3
11.5
RESPIRATORY
Cough
2.5
3.3
2.5
Dyspnea
7.4
9.2
9.8
Overall, discontinuation because of unacceptable adverse events was necessary in 17% of the patients, and
occurred in 10% of patients less than two weeks after starting treatment. The most common adverse reactions
leading to discontinuation of Betapace AF were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea
2%, and QT interval prolongation 1.4%.
6.2 Postmarketing Experience
The following adverse drug reactions have been identified during post-approval use of sotalol. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure. Voluntary reports since introduction
include reports (less than one report per 10,000 patients) of: emotional lability, slightly clouded sensorium,
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incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever,
pulmonary edema, hyperlipidemia, myalgia, pruritis, alopecia.
7 DRUG INTERACTIONS
7.1 Antiarrhythmics and other QT Prolonging Drugs
Sotalol has not been studied with other drugs that prolong the QT interval such as antiarrhythmics, some
phenothiazines, tricyclic antidepressants, certain oral macrolides and certain quinolone antibiotics. Discontinue
Class I or Class III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia
antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (for example,
amiodarone) are not recommended as concomitant therapy with Betapace/Betapace AF, because of their
potential to prolong refractoriness [see Warnings and Precautions (5.2)]. There is only limited experience with
the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with
the use of other beta-blocking agents concomitantly with Betapace/Betapace AF.
7.2 Digoxin
Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear
whether this represents an interaction or is related to the presence of CHF, a known risk factor for
proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow
atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
7.3 Calcium-Channel Blocking Drugs
Sotalol and calcium-blocking drugs can be expected to have additive effects on atrioventricular conduction or
ventricular function. Monitor such patients for evidence of bradycardia and hypotension.
7.4 Catecholamine-Depleting Agents
Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker
may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for evidence of
hypotension and/or marked bradycardia which may produce syncope.
7.5 Insulin and Oral Antidiabetics
Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see
Warnings and Precautions 5.7)].
7.6 Clonidine
Concomitant use with sotalol increases the risk of bradycardia. Because beta-blockers may potentiate the
rebound hypertension sometimes observed after clonidine discontinuation, withdraw sotalol several days before
the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.
7.7 Antacids
Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium
hydroxide.
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Sotalol has been shown to cross the
placenta, and is found in amniotic fluid. In animal studies there was no increase in congenital anomalies, but an
increase in early resorptions occurred at sotalol doses 18 times the maximum recommended human dose
(MRHD, based on surface area). Animal reproductive studies are not always predictive of human response.
Reproduction studies in rats and rabbits during organogenesis at 9 and 7 times the MRHD (based on surface
area), respectively, did not reveal any teratogenic potential associated with sotalol. In rabbits, a dose of sotalol 6
times the MRHD produced a slight increase in fetal death as well as maternal toxicity. This effect did not occur
at sotalol dose 3 times the MRHD. In rats a sotalol dose 18 times the MRHD increased the number of early
resorptions, while a dose 2.5 times the MRHD, produced no increase in early resorptions.
8.3 Nursing Mothers
Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk.
Discontinue nursing on Betapace/Betapace AF.
8.4 Pediatric Use
The safety and effectiveness of sotalol in children have not been established. However, the Class III
electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects
(QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3
days and 12 years old [see Dosage and Administration (2.4) and Clinical Pharmacology (12.2)].
8.6 Renal Impairment
Sotalol is mainly eliminated via the kidneys. Dosing intervals should be adjusted based on creatinine clearance
[see Dosage and Administration (2.5)].
10 OVERDOSAGE
Intentional or accidental overdosage with sotalol has resulted in death.
Symptoms and Treatment of Overdosage
The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm
and hypoglycemia. In cases of massive intentional overdosage (2–16 grams) of sotalol the following clinical
findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes,
ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should
be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful
for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are
normalized and the heart rate returns to levels >50 bpm.
The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination
phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the
hypotension. In addition, if required, the following therapeutic measures are suggested:
Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or
transvenous cardiac pacing.
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Heart Block: (second and third degree) transvenous cardiac pacemaker.
Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be
useful.
Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2
receptor stimulants may be required.
Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.
11 DESCRIPTION
Betapace/Betapace AF contains sotalol hydrochloride, an antiarrhythmic drug with Class II (beta
adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. Betapace is
supplied as a light-blue, capsule-shaped tablet for oral administration. Betapace AF is supplied as a white,
capsule-shaped tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular
weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in
chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl)
amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3 S∙HCl
and is represented by the following structural formula: structural formula
Betapace Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose, starch, stearic
acid, magnesium stearate, colloidal silicon dioxide, and FD&C blue color #2 (aluminum lake, conc.).
Betapace AF Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose, starch,
stearic acid, magnesium stearate, and colloidal silicon dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential
duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have
similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking
activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and
maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing
activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects
are seen only at daily doses of 160 mg and above.
In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m2 body surface area
(BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses
≥ 90 mg/m2 in children.
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12.2 Pharmacodynamics
Cardiac Electrophysiological Effects
Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well
as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows
heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle
and conduction tissue.
In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus
cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The
Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic
action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio
ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral
doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40–100 msec in QT and
10–40 msec in QTc [See Warnings and Precautions (5.1)]. No significant alteration in QRS interval is
observed.
In a small study (n=25) of patients with implanted defibrillators treated concurrently with Betapace, the average
defibrillatory threshold was 6 joules (range 2–15 joules) compared to a mean of 16 joules for a nonrandomized
comparative group primarily receiving amiodarone.
Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged
between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily
doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total 9 doses. During steady-state, the respective
average increases above baseline of the QTc interval were 2, 14, and 29 msec at the 3 dose levels. The
respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose
levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children
(BSA<0.33 m2) showed a tendency for larger Class III effects (ΔQTc) and an increased frequency of
prolongations of the QTc interval as compared with larger children (BSA ≥0.33 m2). The beta-blocking effects
also tended to be greater in the smaller children (BSA <0.33 m2). Both the Class III and beta-blocking effects of
sotalol were linearly related to the plasma concentrations.
Hemodynamics
In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection
fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice
daily of Betapace produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-
dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant
increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart
failure. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11
patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work
index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by
Betapace, and total peripheral resistance increases by a small amount.
In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures.
Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in
patients with marginal cardiac compensation [see Warnings and Precautions (5.3)].
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12.3 Pharmacokinetics
The pharmacokinetics of the d and l enantiomers of sotalol are essentially identical.
Absorption
In healthy subjects, the oral bioavailability of sotalol is 90–100%. After oral administration, peak plasma
concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2–3
days (that is, after 5–6 doses when administered twice daily). Over the dosage range 160–640 mg/day sotalol
displays dose proportionality with respect to plasma concentrations. When administered with a standard meal,
the absorption of sotalol was reduced by approximately 20% compared to administration in fasting state.
Distribution
Sotalol does not bind to plasma proteins. Distribution occurs to a central (plasma) and to a peripheral
compartment. Sotalol crosses the blood brain barrier poorly.
Metabolism
Sotalol is not metabolized and is not expected to inhibit or induce any CYP450 enzymes.
Excretion
Excretion of sotalol is predominantly via the kidney in the unchanged form, and therefore lower doses are
necessary in conditions of renal impairment [see Dosage and Administration (2.5)]. The mean elimination half-
life of sotalol is 12 hours. Dosing every 12 hours results in trough plasma concentrations which are
approximately one-half of those at peak.
Specific Populations
Pediatric: The combined analysis of a single-dose study and a multiple-dose study with 59 children, aged
between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30
mg/m2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 were
administered every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on
average between 2–3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours.
Steady-state was reached after 1–2 days. The average peak to trough concentration ratio was 2. BSA was the
most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children
(BSA<0.33m2) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug
concentration profile. The intersubject variation for oral clearance was 22%.
Geriatric: Age does not significantly alter the pharmacokinetics of Betapace/Betapace AF, but impaired renal
function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug
accumulation.
Renal Impairment: Sotalol is mainly eliminated via the kidneys through glomerular filtration and to a small
degree by tubular secretion. There is a direct relationship between renal function, as measured by serum
creatinine or creatinine clearance, and the elimination rate of sotalol. The half-life of sotalol is prolonged (up to
69 hours) in anuric patients. Doses or dosing intervals should be adjusted based on creatinine clearance [see
Dosage and Administration (2.5)].
Hepatic Impairment: Patients with hepatic impairment show no alteration in clearance of sotalol.
Drug-Drug Interactions:
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Antacids: Administration of oral sotalol within 2 hours of antacids may result in a reduction in Cmax and AUC
of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest.
Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or
pharmacodynamics of sotalol.
No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed in rats during a 24-month study at 137–275 mg/kg/day
(approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the
MRHD as mg/m2) or in mice, during a 24-month study at 4141–7122 mg/kg/day (approximately 450–750 times
the MRHD as mg/kg or 36–63 times the MRHD as mg/m2).
Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.
No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times
the MRHD as mg/kg or 18 times the MRHD as mg/m2) prior to mating, except for a small reduction in the
number of offspring per litter.
Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7
times the MRHD as mg/m2), respectively, did not reveal any teratogenic potential associated with sotalol HCl.
In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as
mg/m2) produced a slight increase in fetal death, and maternal toxicity. Eight times the maximum dose (80
mg/kg/day or 3 times the MRHD as mg/m2) did not result in an increased incidence of fetal deaths. In rats, 1000
mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m2), increased the number of early
resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), no increase in early
resorptions was noted. However, animal reproduction studies are not always predictive of human response.
14 CLINICAL STUDIES
14.1 Ventricular Arrhythmias
Betapace (sotalol hydrochloride) has been studied in life-threatening and less severe arrhythmias. In patients
with frequent premature ventricular complexes (VPC), Betapace (sotalol hydrochloride) was significantly
superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the
response was dose-related through 640 mg/day with 80–85% of patients having at least a 75% reduction of
VPCs. Betapace was also superior, at the doses evaluated, to propranolol (40–80 mg TID) and similar to
quinidine (200–400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained
ventricular tachycardia/fibrillation (VT/VF)], Betapace was studied acutely [by suppression of programmed
electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and,
in acute responders, chronically.
In a double-blind, randomized comparison of Betapace and procainamide given intravenously (total of 2 mg/kg
Betapace vs. 19 mg/kg of procainamide over 90 minutes), Betapace suppressed PES induction in 30% of
patients vs. 20% for procainamide (p=0.2).
In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also
inducible by PES, the effectiveness acutely and chronically of Betapace was compared with that of 6 other
drugs (procainamide, quinidine, mexiletine, propafenone, imipramine and pirmenol). Overall response, limited
to first randomized drug, was 39% for Betapace and 30% for the pooled other drugs. Acute response rate for
first drug randomized using suppression of PES induction was 36% for Betapace vs. a mean of 13% for the
other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of
NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), Betapace yielded 41% response
vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as
effective (by either PES or Holter), Betapace, when compared to the pool of other drugs, had the lowest two-
year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest
withdrawal rate (38% vs. about 75–80%). The most commonly used doses of Betapace in this trial were 320–
480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.
It cannot be determined, however, in the absence of a controlled comparison of Betapace vs. no pharmacologic
treatment (for example, in patients with implanted defibrillators) whether Betapace response causes improved
survival or identifies a population with a good prognosis.
Betapace has not been shown to enhance survival in patients with ventricular arrhythmias.
14.2 Clinical Studies in Supra-ventricular Arrhythmias
Betapace AF has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients
with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.
In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients
with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of Betapace AF (80 mg, 120 mg
and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine
clearance (40-60 mL/min) the same doses were given once daily. Patients were excluded for the following
reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-
tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was
associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months;
congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving
potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors;
uncorrected hypokalemia (serum potassium <3.5 meq/L) or hypomagnesemia (serum magnesium <1.5 meq/L);
received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long
QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of
ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving
treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-
White (WPW) syndrome. If the QT interval increased to ≥520 msec (or JT ≥430 msec if QRS >100 msec) the
drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No
structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the
patients because of reduced creatinine clearance.
Betapace AF was shown to prolong the time to the first symptomatic, ECG-documented recurrence of
AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was
more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were
given twice or once daily, depending on renal function. The results are shown in Figure 2, Table 7 and Table 8.
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2: Study 1 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since
Randomization graph
Table 7: Study 1 – Patient Status at 12 Months
Placebo
Betapace AF Dose
80 mg
120 mg
160 mg
Randomized
69
59
63
62
On treatment in
NSR at 12
months without
recurrencea
23%
22%
29%
23%
Recurrenceab
67%
58%
49%
42%
D/C for AEs
6%
12%
18%
29%
a Symptomatic AFIB/AFL
b Efficacy endpoint of Study 1; study treatment stopped.
Note that columns do not add up to 100% due to discontinuations (D/C) for “other” reasons.
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8: Study 1 – Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs.
Placebo) at 12 Months
Placebo
n=69
Betapace AF Dose
80 mg
n=59
120 mg
n=63
160 mg
n=62
P-value vs. placebo
0.325
0.018
0.029
Relative Risk (RR) to placebo
0.81
0.59
0.59
Median time to recurrence (days)
27
106
229
175
Discontinuation because of adverse events was dose related.
In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232
patients with chronic AFIB, Betapace AF was titrated over a dose range from 80 mg/day to 320 mg/day. The
patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present
in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of
4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140
msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant
renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open
heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, ≥ 3
DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment.
After successful cardioversion patients were randomized to receive placebo (n=114) or Betapace AF (n=118), at
a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily,
but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated
patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%)
and 80 mg twice daily (16%).
Tables 9 and 10 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB
and a reduced risk of recurrence at 6 months compared to placebo.
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 9: Study 2 – Patient Status at 6 Months
Placebo
n=114
Betapace AF
n=118
On treatment in NSR at 6
months without recurrencea
29%
45%
Recurrenceab
67%
49%
D/C for AEs
3%
6%
Death
1%
a Symptomatic or asymptomatic AFIB/AFL
b Efficacy endpoint of Study 2; study treatment stopped.
Table 10: Study 2 – Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk
(vs. Placebo) at 6 Months
Placebo
n=114
Betapace AF
n=118
P-value vs. placebo
0.002
Relative Risk (RR) to placebo
0.55
Median time to recurrence (days)
44
>180
Figure 3: Study 2 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since
Randomization graph
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3 Clinical Studies in Patients with Myocardial Infarction
In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456); Betapace
(sotalol hydrochloride) was given as a non-titrated initial dose of 320 mg once daily. Betapace did not produce a
significant increase in survival (7.3% mortality on Betapace vs. 8.9% on placebo, p=0.3), but overall did not
suggest an adverse effect on survival. There was, however, a suggestion of an early (i.e., first 10 days) excess
mortality (3% on Betapace vs. 2% on placebo).
In a second small trial (n=17 randomized to Betapace) where Betapace was administered at high doses (for
example, 320 mg twice daily) to high-risk post-infarction patients (ejection fraction <40% and either >10
VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within
two weeks of initiating Betapace.
16 HOW SUPPLIED/STORAGE AND HANDLING
Betapace (sotalol hydrochloride); capsule-shaped light-blue scored tablets, imprinted with the strength and
“BETAPACE,” are available as follows:
NDC 70515-105-10 80 mg strength, bottle of 100
NDC 70515-109-10 120 mg strength, bottle of 100
NDC 70515-106-10 160 mg strength, bottle of 100
Betapace AF (sotalol hydrochloride); capsule-shaped white scored tablets, imprinted with the strength and
“BHCP” are available as follows:
NDC 70515-115-06 80 mg strength, bottle of 60
NDC 70515-119-06 120 mg strength, bottle of 60
NDC 70515-116-06 160 mg strength, bottle of 60
Store at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [See USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
• Advise patients to contact their health care provider in the event of syncope, pre-syncopal symptoms or
cardiac palpitations.
• Advise patients that their electrolytes and ECG will be monitored during treatment [see Warnings and
Precautions (5.1)].
• Advise patients to contact their healthcare provider in the event of conditions that could lead to
electrolyte changes such as severe diarrhea, unusual sweating, vomiting, less appetite than normal or
excessive thirst [see Warnings and Precautions (5.1)].
• Advise patients not to change the Betapace/Betapace AF dose prescribed by their healthcare provider.
• Advise patients that they should not miss a dose, but if they do miss a dose they should not double the
next dose to compensate for the missed dose: they should take the next dose at the regularly scheduled
time [see Dosage and Administration (2)].
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Advise patients to not interrupt or discontinue Betapace/Betapace AF without their physician’s advice,
that they should get their prescription for sotalol filled and refilled on time so they do not interrupt
treatment [see Dosage and Administration (2)].
• Advise patients to not start taking other medications without first discussing new medications with their
healcare provider.
• Advice patients that they should avoid taking Betapace/Betapace AF within two hours of taking antacids
that contain aluminum oxide or magnesium hydroxide [see Drug Interactions (7.7)].
©2016, Covis Pharma. All rights reserved.
Manufactured for: company logo
Covis Pharma
Zug, 6300 Switzerland
Made in Finland
Rev. 05/2016
Reference ID: 3929060
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:11.971495
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019865s021lbl.pdf', 'application_number': 19865, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
11,798
|
custom-source
|
2025-02-12T13:46:12.035096
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/19-865S010_Betapace_prntlbl.pdf', 'application_number': 19865, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
|
11,801
|
Directions
■ do not take more than directed
(see overdose warning)
Drug Facts (cont nued)
Other information
■ store at 20-25°C (68-77°F) Avoid excessive heat
40°C (104°F)
■ do not use if carton is opened or neck wrap or
foil inner seal imprinted with “Safety Seal®”
is broken
■ see end panel for lot number and expiration date
Inactive ingredients
carnauba wax corn starch hydroxyethyl cellulose
hypromellose magnesium stearate microcrystalline
cellulose povidone powdered cellulose pregelatinized
starch sodium starch glycolate titanium dioxide triacetin
Questions or comments?
call 1-877-895-3665 (English) or
1-888-466-8746 (Spanish)
adults
■ take 2 caplets every 8 hours
with water
■ swallow whole – do not crush chew
or dissolve
■ do not take more than 6 caplets in
24 hours
■ do not use for more than 10 days
unless directed by a doctor
under
18 years
of age
■ ask a doctor
Drug Facts
Warnings
Alcohol warning: f you consume 3 or more alcoholic
drinks every day ask your doctor whether you should
take acetaminophen or other pain relievers or fever
reducers Acetaminophen may cause liver damage
Uses
■ temporarily relieves minor aches and pains due to
■ arthritis
■ the common cold
■ headache
■ toothache
■ muscular aches
■ backache
■ menstrual cramps
■ temporarily reduces fever
Do not use
■ if you are allergic to acetaminophen or any of the
inactive ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur
■ redness or swelling is present
These could be signs of a serious condition
If pregnant or breast-feeding, ask a health professional
before use
Keep out of reach of children.
Overdose warning Taking more than the recommended
dose (overdose) may cause liver damage n case of
overdose get medical help or contact a Poison Control
Center right away (1-800-222-1222) Quick medical
attention is critical for adults as well as for children even
if you do not notice any signs or symptoms
Active ingredient Purpose
(in each caplet)
Acetaminophen 650 mg
Pain reliever/fever reducer
What makes Tylenol® Arthritis Pain Extended Release Caplets
different?
• Uses a unique, patented bi-layer caplet. The first layer dissolves
quickly to provide prompt relief while the second layer is time released
to provide up to 8 hours of relief.
• For more information or questions, visit our web site www.tylenol.com.
• The makers of Tylenol® do not manufacture store brands.
CTN Ty Arth Pain
February 9, 2009
EXP
XXXXXXX
Contains No Aspirin
®
150 CAPLETS 650 mg each
Caplets*
*Capsule-Shaped Tablets
For The Temporary Relief Of Minor Arthritis Pain
Acetaminophen Extended Release Pain Reliever/Fever Reducer
Contains
Push & Turn Cap
Push & Turn Cap
Distributed by: McNeil Consumer Healthcare
DIVISION OF MCNEIL-PPC, INC.
FORT WASHINGTON, PA 19034 USA © MCN-PPC, INC. 2009
Visit us at www.tylenol.com
or call toll-free 1-877-TYLENOL (1-877-895-3665)
U.S. Patent Nos. 4,968,509 and 5,004,613
®
NDC 50580-112-15
150 CAPLETS
650 mg each
Caplets*
*Capsule-Shaped Tablets
For The Temporary Relief
Of Minor Arthritis Pain
Contains
Acetaminophen Extended Release
Pain Reliever/Fever Reducer
L
A
S
T
S
U
P
T
O
C
A
P
L
E
T
S
Push &
Turn Cap
®
NDC 50580-112-15
For The Temporary Relief Of Minor Arthritis Pain
Contains
Acetaminophen Extended Release Pain Reliever/Fever Reducer
Push &
Turn Cap
*Capsule-Shaped Tablets
Caplets*
150 CAPLETS 650 mg each
L
A
S
T
S
U
P
T
O
C
A
P
L
E
T
S
00000000
00000000
(b) (4)
(b) (4)
(b) (4)
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b) (4)
(b) (4)
Dist. by: McNeil Consumer Healthcare, DIVISION OF MCNEIL-PPC, INC.
Active ingredient (in each caplet)
Purpose
Acetaminophen 650 mg..............Pain reliever/fever reducer
Uses ■ temporarily relieves minor aches and pains due to:
■ muscular aches
■ backache
■ headache
■ toothache
■ the common cold
■ menstrual cramps
■ minor pain of arthritis
■ temporarily reduces fever
Warnings
Alcohol warning: If you consume 3 or more alcoholic drinks
every day, ask your doctor whether you should take
acetaminophen or other pain relievers or fever reducers.
Acetaminophen may cause liver damage.
Do not use
■ if you are allergic to acetaminophen or any of the inactive
ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur ■ redness or swelling is present
These could be signs of a serious condition.
If pregnant or breast-feeding, ask a health professional before use.
Keep out of reach of children.
Overdose warning: Taking more than the recommended
dose (overdose) may cause liver damage. In case of
overdose, get medical help or contact a Poison Control
READ THE LABEL
Center right away. (1 800 222 1222) Quick medical
XXXXXX
EXP. DATE:
LOT:
FORT WASHINGTON, PA 19034 USA
©MCN-PPC, INC. 2009
www.tylenol.com U.S. Pat. Nos. 4,968,509 and 5,004,613
®
NDC 50580-297-10
100 CAPLETS 650 mg each
*Take only as directed.
Pain Reliever / Fever Reducer
Acetaminophen Extended Release Pain Reliever
For Up to 8 Hour Relief of Minor Muscular Aches & Pain
Contains
DO NOT USE WITH OTHER MEDICINES
CONTAINING ACETAMINOPHEN
attention is critical for adults as well as for children even
if you do not notice any signs or symptoms.
Directions
■ do not take more than directed (see overdose warning)
Adults and children 12 years and over:
■ take 2 caplets every 8 hours with water
■ swallow whole do not crush, chew or dissolve
■ do not take more than 6 caplets in 24 hours
■ do not use for more than 10 days unless directed
by a doctor
Children under 12 years: ■ do not use
Other information
■ store at 20 25°C (68 77°F). Avoid excessive heat 40°C (104°F).
■ do not use if neck wrap or foil inner seal
imprinted with “Safety Seal®” is broken
Inactive ingredients corn starch, D&C yellow #10
aluminum lake, FD&C red #40 aluminum lake, FD&C yellow
#6 aluminum lake, hydroxyethyl cellulose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol,
povidone, powdered cellulose, pregelatinized starch, sodium
starch glycolate, sucralose, talc, titanium dioxide
Questions or comments?
call 1-877-895-3665 (English) or 1-888-466-8746 (Spanish)
150% OF SIZE ª
00000000
XXXXXX
overdose, get medical help or contact a Poison Control
Center right away. (1-800-222-1222) Quick medical
attention is critical for adults as we l as for children even
if you do not notice any signs or symptoms.
Directions
■ do not take more than directed (see overdose warning)
Adults and children 12 years and over:
■ take 2 caplets every 8 hours with water
■ swa low whole – do not crush, chew or dissolve
■ do not take more than 6 caplets in 24 hours
■ do not use for more than 10 days unless directed
by a doctor
Children under 12 years: ■ do not use
Other information
■ s ore at 20-25°C (68 – 77°F). Avoid excessive heat 40°C (104°F)
■ do not use if neck wrap or foil inner seal
imprinted with “Safety Seal®” is broken
Inactive ingredients corn starch, D&C yellow #10
aluminum lake, FD&C red #40 aluminum lake, FD&C ye low
#6 aluminum lake, hydroxyethyl cellulose, magnesium stearate,
microcrysta line cellulose, polyethylene glycol, polyvinyl alcohol,
povidone, powdered cellulose, pregelatinized starch, sodium
starch glycolate, sucralose, talc, titanium dioxide
Questions or comments?
call 1-877-895-3665 (English) or 1-888-466-8746 (Spanish)
Active ingredient (in each caplet)
Purpose
Acetaminophen 650 mg..............Pain reliever/fever reducer
Uses ■ temporar ly relieves minor aches and pains due to:
■ muscular aches
■ backache
■ headache
■ toothache
■ the common cold
■ menstrual cramps
■ minor pain of arthritis
■ temporarily reduces fever
Warnings
Alcohol warning: If you consume 3 or more alcoholic drinks
every day, ask your doctor whether you should take
acetaminophen or other pain relievers or fever reducers.
Acetaminophen may cause liver damage.
Do not use
■ if you are a lergic to acetaminophen or any of the inactive
ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur ■ redness or swelling is present
These could be signs of a serious condition.
If pregnant or breast-feeding, ask a health professional before use.
Keep out of reach of children.
Overdose warning: Taking more than the recommended
dose (overdose) may cause liver damage. In case of
EXP. DATE:
LOT:
Dist. by: McNeil Consumer Healthcare, DIVISION OF MCNEIL-PPC, INC.
FORT WASHINGTON, PA 19034 USA
©MCN-PPC, INC. 2009
www.tylenol.com U.S. Pat. Nos. 4,968,509 and 5,004,613
READ THE LABEL
®
NDC 50580-297-10
100 CAPLETS 650 mg each
*Take only as directed.
Pain Reliever / Fever Reducer
Acetaminophen Extended Release Pain Reliever
For Up to 8 Hour Relief of Minor Muscular Aches & Pain
Contains
DO NOT USE WITH OTHER MEDICINES
CONTAINING ACETAMINOPHEN
(b) (4)
(b) (4)
LBL Ty 8 Hour
February 9, 2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b) (4)
(b) (4)
®
NDC 50580-297-10
®
Caplets*
Caplets*
*Capsule-Shaped Tablets
*Capsule-Shaped Tablets
Contains No Aspirin
100 CAPLETS 650 mg each
*Take only as directed.
Pain Reliever
Fever Reducer
Acetaminophen Extended Release Pain Reliever
Contains
For Up to 8 Hour Relief of Minor Muscular Aches & Pain
Acetaminophen Extended Release Pain Reliever
Contains
For Up to 8 Hour Relief of Minor Muscular Aches & Pain
®
*Take only as directed.
Pain Reliever
Fever Reducer
Acetaminophen Extended Release Pain Reliever
Contains
For Up to 8 Hour Relief of Minor Muscular Aches & Pain
Caplets*
*Capsule-Shaped Tablets
100 CAPLETS 650 mg each
Directions
■
do not take more than directed (see overdose warning)
XXXXXXX
What makes Tylenol® 8 Hour Extended Relief
Caplets different?
• Uses a unique, patented bi-layer caplet. The first layer
dissolves quickly to provide prompt relief while the second
layer is time released to provide up to 8 hours of relief.
• For more information or questions, visit our website
www.tylenol.com.
• The makers of Tylenol® do not manufacture store brands.
Drug Facts
Active ingredient
Purpose
(in each caplet)
Pain reliever/
Acetaminophen 650 mg.................................fever reducer
Warnings
Alcohol warning: If you consume 3 or more alcoholic
drinks every day, ask your doctor whether you should take
acetaminophen or other pain relievers or fever reducers.
Acetaminophen may cause liver damage.
Do not use
■ if you are allergic to acetaminophen or any of the
inactive ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur
■ redness or swelling is present
These could be signs of a serious condition.
If pregnant or breast-feeding, ask a health professional
before use.
Keep out of reach of children.
Overdose warning: Taking more than the recommended
dose (overdose) may cause liver damage. In case of
overdose, get medical help or contact a Poison Control
Center right away. (1-800-222-1222) Quick medical attention
is critical for adults as well as for children even if you do not
notice any signs or symptoms.
Other information
■
store at 20-25°C (68-77°F). Avoid excessive heat 40°C (104°F).
■
do not use if carton is opened or neck wrap or foil
inner seal imprinted with “Safety Seal®” is broken
■ see end panel for lot number and expiration date
Drug Facts (continued)
Questions or comments?
call 1-877-895-3665 (English) or 1-888-466-8746 (Spanish)
children under
12 years
■
do not use
adults and
children
12 years
and over
■
take 2 caplets every 8 hours with water
■
swallow whole – do not crush, chew
or dissolve
■
do not take more than 6 caplets in
24 hours
■
do not use for more than 10 days
unless directed by a doctor
Inactive ingredients
corn starch, D&C yellow #10 aluminum lake, FD&C red #40
aluminum lake, FD&C yellow #6 aluminum lake,
hydroxyethyl cellulose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polyvinyl alcohol, povidone,
powdered cellulose, pregelatinized starch, sodium starch
glycolate, sucralose, talc, titanium dioxide
Uses
■ temporarily relieves minor aches and pains due to:
■ muscular aches
■ backache
■ headache
■ toothache
■ the common cold
■ menstrual cramps
■ minor pain of arthritis
■ temporarily reduces fever
Distributed by:
MCNEIL–PPC, INC.
FORT WASHINGTON, PA 19034 USA ©MCN-PPC, INC. 2009
Visit us at www.tylenol.com or call 1-877-TYLENOL
(1-877-895-3665)
U.S. Pat. Nos. 4,968,509 and 5,004,613
EXP
00000000
00000000
CTN Ty 8 Hour
February 9, 2009
(b) (4)
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b) (4)
(b) (4)
(b) (4)
®
NDC 50580-112-15
150 CAPLETS
650 mg each
*Capsule-Shaped Tablets
Caplets
DO NOT USE WITH OTHER MEDICINES
CONTAINING ACETAMINOPHEN
READ THE LABEL
For The Temporary Relief Of Minor Arthritis Pain
Contains
Acetaminophen Extended Release Pain Reliever/Fever Reducer
Active ingredient (in each caplet) Purpose
Acetaminophen 650 mg.................Pain reliever/fever reducer
Uses
■ temporarily relieves minor aches and pains due to:
■ arthritis
■ the common cold
■ headache
■ toothache
■ muscular aches
■ backache
■ menstrual cramps
■ temporarily reduces fever
Warnings
Alcohol warning: If you consume 3 or more alcoholic drinks
every day, ask your doctor whether you should take
acetaminophen or other pain relievers or fever reducers.
Acetaminophen may cause liver damage.
Do not use
■ if you are allergic to acetaminophen or any of the inactive
ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur
■ redness or swelling is present
These could be signs of a serious condition.
If pregnant or breast feeding, ask a health professional
before use. Keep out of reach of children.
Overdose warning: Taking more than the recommended dose
(overdose) may cause liver damage. In case of overdose, get
medical help or contact a Poison Control Center right away.
(1 800 222 1222) Quick medical attention is critical for adults
as well as for children even if you do not notice any signs
or symptoms.
Directions
■ do not take more than directed (see overdose warning)
Adults:
■ take 2 caplets every 8 hours with water
■ swallow whole
do not crush, chew or dissolve
■ do not take more than 6 caplets in 24 hours
■ do not use for more than 10 days unless directed by a doctor
Under 18 years of age:
■ ask a doctor
Other information
■ store at 20 25°C (68 77°F). Avoid excessive heat
40°C (104°F).
■ do not use if neck wrap or foil inner seal imprinted with
“Safety Seal®” is broken
Inactive ingredients
carnauba wax, corn starch, hydroxyethyl cellulose,
hypromellose, magnesium stearate, microcrystalline cellulose,
povidone, powdered cellulose, pregelatinized starch, sodium
starch glycolate, titanium dioxide, triacetin
Questions or comments?
call 1 877 895 3665 (English) or
1 888 466 8746 (Spanish)
Distributed by: McNeil Consumer Healthcare
DIVISION OF MCNEIL–PPC, INC.
FORT WASHINGTON, PA 19034 USA
© MCN-PPC, INC. 2009
www.tylenol.com
U.S. Patent Nos. 4,968,509 and 5,004,613
EXP.
LOT:
XXXXXX
120 % OF SIZE ª
00000000
®
NDC 50580-112-15
150 CAPLETS
650 mg each
*Capsule-Shaped Tablets
Caplets
DO NOT USE WITH OTHER MEDICINES
CONTAINING ACETAMINOPHEN
READ THE LABEL
For The Temporary Relief Of Minor Arthritis Pain
Contains
Acetaminophen Extended Release Pain Reliever/Fever Reducer
Active ingredient (in each caplet) Purpose
Acetaminophen 650 mg................. Pain reliever/fever reducer
Uses
■ temporarily relieves minor aches and pains due to:
■ arthritis
■ the common cold
■ headache
■ toothache
■ muscular aches
■ backache
■ menstrual cramps
■ temporarily reduces fever
Warnings
Alcohol warning: If you consume 3 or more alcoholic drinks
every day, ask your doctor whether you should take
acetaminophen or other pain relievers or fever reducers.
Acetaminophen may cause liver damage.
Do not use
■ if you are allergic to acetaminophen or any of the inactive
ingredients in this product
■ with any other product containing acetaminophen
Stop use and ask a doctor if
■ pain gets worse or lasts for more than 10 days
■ fever gets worse or lasts for more than 3 days
■ new symptoms occur
■ redness or swelling is present
These could be signs of a serious condition.
If pregnant or breast-feeding, ask a health professional
before use. Keep out of reach of children.
Overdose warning: Taking more than the recommended dose
(overdose) may cause liver damage. In case of overdose, get
medical help or contact a Poison Control Center right away.
(1-800-222-1222) Quick medical attention is critical for adults
as well as for children even if you do not notice any signs
or symptoms.
Directions
■ do not take more than directed (see overdose warning)
Adults:
■ take 2 caplets every 8 hours with water
■ swallow whole – do not crush, chew or dissolve
■ do not take more than 6 caplets in 24 hours
■ do not use for more than 10 days unless directed by a doctor
Under 18 years of age:
■ ask a doctor
Other information
■ store at 20-25°C (68-77°F). Avoid excessive heat
40°C (104°F).
■ do not use if neck wrap or foil inner seal imprinted with
“Safety Seal®” is broken
Inactive ingredients
carnauba wax, corn starch, hydroxyethyl cellulose,
hypromellose, magnesium stearate, microcrystalline cellulose,
povidone, powdered cellulose, pregelatinized starch, sodium
starch glycolate, titanium dioxide, triacetin
Questions or comments?
call 1-877-895-3665 (English) or
1-888-466-8746 (Spanish)
Distributed by: McNeil Consumer Healthcare
DIVISION OF MCNEIL–PPC, INC.
FORT WASHINGTON, PA 19034 USA
© MCN-PPC, INC. 2009
www.tylenol.com
U.S. Patent Nos. 4,968,509 and 5,004,613
EXP.
LOT:
XXXXXX
(b) (4)
LBL Ty Arth Pain
February 9, 2009 ¬
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------
---------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
/s/
Joel Schiffenbauer
6/17/2009 07:05:30 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
2025-02-12T13:46:12.574496
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019872s031Lbl.pdf', 'application_number': 19872, 'submission_type': 'SUPPL ', 'submission_number': 31}
|
11,800
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19872slr012_tylenol_lbl.pdf', 'application_number': 19872, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
11,802
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
12/20/2013
Reference ID: 3426161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:12.676040
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019872Orig1s039lbl.pdf', 'application_number': 19872, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,804
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
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/s/
----------------------------------------------------
KAREN M MAHONEY
12/12/2014
Reference ID: 3672023
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:12.832608
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019872Orig1s041lbl.pdf', 'application_number': 19872, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
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_______________________________________________________________________________________________________________________________________
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
MESNEX safely and effectively. See full prescribing information for
MESNEX.
MESNEX (mesna) injection, for intravenous use
MESNEX (mesna) tablets, for oral use
Initial U.S. Approval: 1988
----------------------------INDICATIONS AND USAGE--------------------------
MESNEX is a cytoprotective agent indicated as a prophylactic agent in
reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1)
Limitation of Use:
MESNEX is not indicated to reduce the risk of hematuria due to other
pathological conditions such as thrombocytopenia. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
MESNEX may be given on a fractionated dosing schedule of three bolus
intravenous injections or a single bolus injection followed by two oral
administrations of MESNEX Tablets as outlined below. The dosing schedule
should be repeated on each day that ifosfamide is administered. When the
dosage of ifosfamide is adjusted, the ratio of MESNEX to ifosfamide should
be maintained. (2)
Intravenous Dosing Schedule:
0 Hours
4 Hours
8 Hours
Ifosfamide
1.2 g/m2
-
-
MESNEX Injection
240 mg/m2
240 mg/m2
240 mg/m2
Intravenous and Oral Dosing Schedule:
0 Hours
2 Hours
6 Hours
Ifosfamide
1.2 g/m2
-
-
MESNEX Injection
240 mg/m2
-
-
MESNEX Tablets
-
480 mg/m2
480 mg/m2
Maintain sufficient urinary output, as required for ifosfamide treatment, and
monitor urine for the presence of hematuria. (2.3)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
•
Injection: 1g (100 mg/mL) Multidose vials (3)
•
Tablets: 400 mg with functional score (3)
-------------------------------CONTRAINDICATIONS-----------------------------
•
Known hypersensitivity to MESNEX or to any of the excipients,
including benzyl alcohol. (4)
-----------------------WARNINGS AND PRECAUTIONS---------------------
•
Hypersensitivity reactions: Anaphylactic reactions have been reported.
Less severe hypersensitivity reactions may also occur. Monitor patients. If
a reaction occurs, discontinue MESNEX and provide supportive care. (5.1)
•
Dermatologic toxicity: Skin rash with eosinophilia and systemic
symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis
have occurred. Skin rash, urticaria, and angioedema have also been seen.
Monitor patients. If a reaction occurs, discontinue MESNEX and provide
supportive care. (5.2)
•
Benzyl alcohol toxicity: The preservative benzyl alcohol has been
associated with serious adverse reactions and death in neonates and
premature infants. Avoid use in neonates, premature, and low-birth weight
infants. (5.3)
•
Laboratory test alterations: False positive tests for urinary ketones and
interference with enzymatic CPK activity tests have been seen. (5.4)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions (> 10%) when MESNEX is given with
ifosfamide are nausea, vomiting, constipation, leukopenia, fatigue, fever,
anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia,
abdominal pain, headache, alopecia, and somnolence. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Baxter
Healthcare at 1-866-888-2472, or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS--------------------
•
Pregnancy: Use only if clearly needed. (8.1)
•
Nursing mothers: Women should not breastfeed during therapy. (8.3)
•
Geriatric use: Dose selection should be cautious. (8.5)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling
Revised: 03/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Intravenous Dosing
2.2 Intravenous and Oral Dosing
2.3 Monitoring of Hematuria
2.4 Preparation for Intravenous Administration and Stability
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
5.2 Dermatologic Toxicity
5.3 Benzyl Alcohol Toxicity
5.4 Laboratory Test Interferences
5.5 Use in Patients with a History of Adverse Reactions to Thiol
Compounds
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Use in Patients with Renal Impairment
8.7 Use in Patients with Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Intravenous MESNEX
14.2 Oral MESNEX
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
MESNEX is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic
cystitis.
Reference ID: 3472090
Limitation of Use:
MESNEX is not indicated to reduce the risk of hematuria due to other pathological conditions such as
thrombocytopenia.
2 DOSAGE AND ADMINISTRATION
2.1 Intravenous Dosing
MESNEX may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined
below.
MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage
weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of
ifosfamide. The total daily dose of MESNEX is 60% of the ifosfamide dose. The recommended dosing schedule
is outlined below in Table 1.
Table 1. Recommended Intravenous Dosing Schedule
0 Hours
4 Hours
8 Hours
Ifosfamide
1.2 g/m2
-
-
MESNEX Injection1
240 mg/m2
240 mg/m2
240 mg/m2
1The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or
decreased, the ratio of MESNEX to ifosfamide should be maintained.
2.2 Intravenous and Oral Dosing
MESNEX may be given on a fractionated dosing schedule of a single bolus injection followed by two oral
administrations of MESNEX tablets as outlined below.
MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage
(w/w) at the time of ifosfamide administration. MESNEX tablets are given orally in a dosage equal to 40% of
the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of MESNEX is 100% of
the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.
Reference ID: 3472090
2
Table 2. Recommended Intravenous and Oral Dosing Schedule
0 Hours
2 Hours
6 Hours
Ifosfamide
1.2 g/m2
-
-
MESNEX injection1
240 mg/m2
-
-
MESNEX tablets
-
480 mg/m2
480 mg/m2
1The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or
decreased, the ratio of MESNEX to ifosfamide should be maintained.
The efficacy and safety of this ratio of intravenous and oral MESNEX has not been established as being
effective for daily doses of ifosfamide higher than 2 g/m2 .
Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous
MESNEX.
2.3 Monitoring for Hematuria
Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor
urine for the presence of hematuria. If severe hematuria develops when MESNEX is given according to the
recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.
2.4 Preparation for Intravenous Administration and Stability
Preparation
Determine the volume of MESNEX injection for the intended dose.
Dilute the volume of MESNEX injection for the dose in any of the following fluids to obtain a final
concentration of 20 mg/mL:
• 5% Dextrose Injection, USP
• 5% Dextrose and 0.2% Sodium Chloride Injection, USP
• 5% Dextrose and 0.33% Sodium Chloride Injection, USP
• 5% Dextrose and 0.45% Sodium Chloride Injection, USP
• 0.9% Sodium Chloride Injection, USP
• Lactated Ringer’s Injection, USP
Stability
The MESNEX injection multidose vials may be stored and used for up to 8 days after initial puncture.
Store diluted solutions at 25°C (77°F). Use diluted solutions within 24 hours.
Do not mix MESNEX injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen
mustard.
The benzyl alcohol contained in MESNEX injection vials can reduce the stability of ifosfamide. Ifosfamide and
MESNEX may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50
mg/mL. Higher concentrations of ifosfamide may not be compatible with MESNEX and may reduce the
stability of ifosfamide.
Reference ID: 3472090
3
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain
visible particulate matter should not be used.
3 DOSAGE FORMS AND STRENGTHS
• MESNEX injection: 1 g Multidose Vial, 100 mg/mL
• MESNEX tablets: 400 mg film-coated tablets with functional score
4 CONTRAINDICATIONS
MESNEX is contraindicated in patients known to be hypersensitive to MESNEX or to any of the excipients
[see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
MESNEX may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include
fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory
distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological
abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur
with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue
MESNEX and provide supportive care.
5.2 Dermatologic Toxicity
Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions,
consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. MESNEX may cause
skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema,
periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several
months of exposure. Discontinue MESNEX and provide supportive care.
5.3 Benzyl Alcohol Toxicity
Benzyl alcohol, a preservative in MESNEX, has been associated with serious adverse reactions and death
(including gasping syndrome) in neonates, premature, and low-birth weight infants. The minimum amount of
benzyl alcohol at which toxicity may occur is not known. Consider the combined daily metabolic load of benzyl
alcohol from all sources when prescribing MESNEX (10.4 mg benzyl alcohol per mL). Neonates, premature,
and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity.
Monitor patients for signs or symptoms of toxicity. Avoid use in neonates, premature, and low-birth weight
infants [See Use in Specific Populations (8.4)].
5.4 Laboratory Test Interferences
False-Positive Urine Tests for Ketone Bodies
A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside
sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to
Reference ID: 3472090
4
differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet
color that intensifies).
False-Negative Tests for Enzymatic CPK Activity
MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol
compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.
False-Positive Tests for Ascorbic Acid
MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.
5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds
MESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity
reactions to MESNEX and to amifostine, another thiol compound, have been reported. It is not clear whether
patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity
reaction to MESNEX.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling.
• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Dermatological Toxicity [see Warnings and Precautions (5.2)]
• Benzyl Alcohol Toxicity[see Warnings and Precautions (5.3)]
• Laboratory Test Interferences [see Warnings and Precautions (5.4)]
• Use in Patients with a History of Adverse Reactions to Thiol Compounds [see Warnings and
Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
MESNEX adverse reaction data are available from four Phase 1 studies in which single intravenous doses of
600-1200 mg MESNEX Injection without concurrent chemotherapy were administered to a total of 53 healthy
volunteers and single oral doses of 600-2400 mg of MESNEX Tablets were administered to a total of 82 healthy
volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy
volunteers receiving single doses of MESNEX Injection alone were headache, injection site reactions, flushing,
dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like
symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received MESNEX
Tablets alone or intravenous MESNEX followed by repeated doses of MESNEX Tablets, flatulence and rhinitis
were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of
intravenous MESNEX.
Additional adverse reactions in healthy volunteers receiving MESNEX alone included injection site reactions,
abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia,
Reference ID: 3472090
5
myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity
pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers,
MESNEX was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was
generally reversible within one week of administration.
Because MESNEX is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it
is difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the
concomitantly administered cytotoxic agents.
Adverse reactions reasonably associated with MESNEX administered intravenously and orally in four
controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in
Table 3.
Table 3: Adverse Reactions in ≥5% of Patients Receiving MESNEX in combination
with Ifosfamide-containing Regimens
MESNEX Regimen
Intravenous-Intravenous-Intravenous1
Intravenous-Oral-Oral1
N exposed
119 (100.0%)
119 (100%)
Incidence of AEs
101 (84.9%)
106 (89.1%)
Nausea
65 (54.6)
64 (53.8)
Vomiting
35 (29.4)
45 (37.8)
Constipation
28 (23.5)
21 (17.6)
Leukopenia
25 (21.0)
21 (17.6)
Fatigue
24 (20.2)
24 (20.2)
Fever
24 (20.2)
18 (15.1)
Anorexia
21 (17.6)
19 (16.0)
Thrombocytopenia
21 (17.6)
16 (13.4)
Anemia
20 (16.8)
21 (17.6)
Granulocytopenia
16 (13.4)
15 (12.6)
Asthenia
15 (12.6)
21 (17.6)
Abdominal Pain
14 (11.8)
18 (15.1)
Alopecia
12 (10.1)
13 (10.9)
Dyspnea
11 (9.2)
11 (9.2)
Chest Pain
10 (8.4)
11 (9.2)
Hypokalemia
10 (8.4)
11 (9.2)
Diarrhea
9 (7.6)
17 (14.3)
Dizziness
9 (7.6)
5 (4.2)
Headache
9 (7.6)
13 (10.9)
Pain
9 (7.6)
10 (8.4)
Sweating Increased
9 (7.6)
2 (1.7)
Back Pain
8 (6.7)
6 (5.0)
Hematuria
8 (6.7)
7 (5.9)
Injection Site Reaction
8 (6.7)
10 (8.4)
Reference ID: 3472090
6
Edema
8 (6.7)
9 (7.6)
Edema Peripheral
8 (6.7)
8 (6.7)
Somnolence
8 (6.7)
12 (10.1)
Anxiety
7 (5.9)
4 (3.4)
Confusion
7 (5.9)
6 (5.0)
Face Edema
6 (5.0)
5 (4.2)
Insomnia
6 (5.0)
11 (9.2)
Coughing
5 (4.2)
10 (8.4)
Dyspepsia
4 (3.4)
6 (5.0)
Hypotension
4 (3.4)
6 (5.0)
Pallor
4 (3.4)
6 (5.0)
Dehydration
3 (2.5)
7 (5.9)
Pneumonia
2 (1.7)
8 (6.7)
Tachycardia
1 (0.8)
7 (5.9)
Flushing
1 (0.8)
6 (5.0)
1Intravenous dosing of ifosfamide and MESNEX followed by either intravenous or oral doses of MESNEX according to the applicable
dosage schedule. [see Dosage and Administration (2)].
6.2 Postmarketing Experience
The following adverse reactions have been reported in the postmarketing experience of patients receiving
MESNEX in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse
reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic
agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency
cannot be made.
Cardiovascular: Hypertension
Gastrointestinal: Dysgeusia
Hepatobiliary: Hepatitis
Nervous System: Convulsion
Respiratory: Hemoptysis
7 DRUG INTERACTIONS
No clinical drug interaction studies have been conducted with MESNEX.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B.
Risk Summary
There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at
oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on
a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the
Reference ID: 3472090
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fetus due to mesna. The incidence of malformations in human pregnancies has not been established for
MESNEX. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major
malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum
is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are
excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a
decision should be made whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl
alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in
pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic
acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates,
premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration,
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure,
hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which
toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients
receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other
medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol
from all sources [see Warnings and Precautions (5.3)].
8.5 Geriatric Use
Clinical studies of MESNEX did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. In general, dose selection for an elderly patient should
be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy. The ratio of ifosfamide to MESNEX should remain unchanged.
8.6 Use in Patients with Renal Impairment
No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of
MESNEX.
8.7 Use in Patients with Hepatic Impairment
No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of
MESNEX.
10 OVERDOSAGE
There is no known antidote for MESNEX.
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In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days.
Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea
and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients
receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or
hydration treatment only.
Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including
mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.
11 DESCRIPTION
MESNEX is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active
ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a
molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:
HS–CH2–CH2SO3–Na+
MESNEX (mesna) injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in
clear glass multidose vials for intravenous administration. MESNEX injection contains 100 mg/mL mesna,
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. MESNEX Injection multidose vials
also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.
MESNEX (mesna) tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They
contain 400 mg mesna. The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose,
lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and
titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting
in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy
ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein
and to other urotoxic metabolites and inhibits their effects on the bladder.
12.3 Pharmacokinetics
Absorption
Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours
for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability
averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma
AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.
Food does not affect the urinary availability of orally administered MESNEX.
Distribution
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Mean apparent volume of distribution (Vd) for mesna is 0.652 ± 0.242 L/kg after intravenous administration
which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).
Metabolism
Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite,
mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous
administration.
Excretion
Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered
dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-
lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23
L/h/kg.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.
Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte
chromosomal aberration assay or the in vivo mouse micronucleus assay.
No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity
were seen in 6-month oral rat studies (≤2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses
approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.
14 CLINICAL STUDIES
14.1 Intravenous MESNEX
Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide
administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid
intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or
macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together
with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and
6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 days, produced hematuria in 31 to
100% of the patients. When MESNEX was administered together with these doses of ifosfamide, the incidence
of hematuria was less than 7%.
Table 4. Percent of MESNEX Patients Developing Hematuria
(≥50 RBC/hpf or macrohematuria)
Study
Conventional Uroprophylaxis
(number of patients)
Standard MESNEX Intravenous
Regimen (number of patients)
Uncontrolled Studies*
Reference ID: 3472090
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Study 1
16% (7/44)
-
Study 2
26% (11/43)
-
Study 3
18% (7/38)
0% (0/21)
Study 4
-
0% (0/32)
Controlled Studies†
Study 5
31% (14/46)
6% (3/46)
Study 6
100% (7/7)
0% (0/8)
*Ifosfamide dose 1.2 g/m2 d x 5
†Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to 5
14.2 Oral MESNEX
Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated
incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study
comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in
patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 was a
randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies,
development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing
hematuria in each of these studies is presented in Table 5.
Table 5. Percent of MESNEX Patients Developing Grade 3 or 4 Hematuria
MESNEX Dosing Regimen
Study
Standard Intravenous
Regimen
(number of patients)
Intravenous + Oral Regimen
(number of patients)
Study 7
0% (0/30)
3.6% (1/28)
Study 8
3.7% (1/27)
4.3% (1/23)
16 HOW SUPPLIED/STORAGE AND HANDLING
MESNEX (mesna) injection 100 mg/mL
• NDC 0338-1305-01
1 g Multidose Vial, Box of 1 vial of 10 mL
• NDC 0338-1305-03
1 g Multidose Vial, Box of 10 vials of 10 mL
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].
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MESNEX (mesna) tablets
• NDC 67108-3565-9
400 mg scored tablets packaged in box of 10 tablets
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information).
• Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or
symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings
and Precautions (5.1)].
• Advise the patient to take MESNEX at the exact time and in the exact amount as prescribed. Advise the
patient to contact their healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if
they miss a dose of oral MESNEX [see Dosage and Administration (2.2)].
• MESNEX does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the
other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their
healthcare provider if his/her urine has turned a pink or red color [see Dosage and Administration (2.3)].
• Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX therapy [see Dosage and
Administration (2.3)].
• Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with
eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have
occurred with MESNEX. Advise the patient to report to their healthcare provider if signs and symptoms
of these syndromes occur [see Warnings and Precautions (5.2)]. company logo
MESNEX (mesna) injection manufactured by:
MESNEX (mesna) tablets manufactured for:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry
1800 ANA DRUG (1-800-262-3784)
Made in Germany
Baxter, MESNEX, and IFEX are trademarks of Baxter International Inc.
Material No. TBD
Reference ID: 3472090
12
13
__________________________________________________________________________________________________________________________________
Patient Information
MESNEX (MES-nex)
(mesna)
tablets
MESNEX (MES-nex)
(mesna)
injection
What is the most important information I should know about MESNEX?
MESNEX can cause serious allergic reactions and skin reactions. These side effects can
happen the first time you are treated with MESNEX, or after several months of treatment with
MESNEX. Stop treatment with MESNEX and call your doctor or go to the nearest hospital
emergency room right away if you develop any of the symptoms listed below:
•
fever
•
swelling of your face, lips, mouth, or
tongue
•
trouble breathing or wheezing
•
itching
•
burning
•
skin rash or hives
•
skin redness or swelling
•
skin blisters or peeling
•
feel lightheaded or faint
•
feel like your heart is racing
•
nausea or vomiting
•
joint or muscle aches
•
mouth sores
See “What are the possible side effects of MESNEX?” for more information about side
effects.
What is MESNEX?
MESNEX is a prescription medicine used to reduce the risk of inflammation and bleeding of the
bladder (hemorrhagic cystitis) in people who receive ifosfamide (a medicine used to treat
cancer).
MESNEX is not for use to reduce the risk of blood in the urine (hematuria) due to other medical
conditions.
It is not known if MESNEX is safe and effective in children.
Who should not receive MESNEX?
Do not take MESNEX if you are allergic to MESNEX or any of the ingredients in MESNEX. See the
end of this leaflet for a complete list of ingredients in MESNEX.
What should I tell my doctor before receiving MESNEX?
Before you receive MESNEX, tell your doctor if you:
•
have any other medical conditions
•
are pregnant or plan to become pregnant. It is not known if MESNEX will harm your
unborn baby.
•
are breastfeeding or plan to breastfeed. It is not known if MESNEX passes into your breast
milk. You and your doctor should decide if you will receive MESNEX or breastfeed. You
should not do both.
Tell your doctor about all the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements.
How will I receive MESNEX?
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14
•
MESNEX is given on the same day that you receive ifosfamide.
•
MESNEX can be given by an intravenous (IV) infusion into a vein or tablets taken by
mouth.
•
You will receive MESNEX in one of two ways:
1. MESNEX intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4
and 8 hours after you receive ifosfamide.
2. MESNEX intravenous (IV) infusion into a vein at the time you receive ifosfamide and
MESNEX tablets taken by mouth 2 and 6 hours after you receive ifosfamide.
•
Take MESNEX tablets at the exact times and the exact dose your doctor tells you to take
it.
•
You may need to take half of a MESNEX tablet for your complete dose. Each tablet has a
groove in the middle that will make it easier to break the tablet in half.
•
During treatment with MESNEX,you should drink 4 to 8 cups of liquid (1 to 2 liters) each
day, whether you receive MESNEX by intravenous infusion or take MESNEX tablets by
mouth.
•
Tell your doctor if you:
o vomit within 2 hours of taking MESNEX tablets by mouth
o miss a dose of MESNEX tablets
o have pink or red colored urine
What are the possible side effects of MESNEX?
MESNEX may cause serious side effects, including:
See “What is the most important information I should know about MESNEX?”
•
MESNEX that is given by intravenous infusion contains the preservative benzyl
alcohol. Benzyl alcohol has been shown to cause serious side effects and death in
newborn, premature, and low-birth weight babies. MESNEX tablets do not contain benzyl
alcohol.
The most common side effects of MESNEX when given with ifosfamide include:
•
nausea
•
vomiting
•
constipation
•
decreased white blood cell count
•
tiredness
•
fever
•
decreased appetite
•
decreased platelet count
•
decreased red blood cell count
•
diarrhea
•
weakness
•
stomach (abdomen) pain
•
headache
•
hair loss
•
sleepiness
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of MESNEX. For more information, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
Reference ID: 3472090
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How should I store MESNEX tablets?
•
Store MESNEX tablets at room temperature between 68°F to 77°F (20°C to 25°C).
Keep MESNEX and all medicines out of the reach of children.
General information about the safe and effective use of MESNEX
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use MESNEX for a condition for which it was not prescribed. Do not give MESNEX
to other people, even if they have the same symptoms that you have. It may harm them. If you
would like more information, talk with your doctor. You can ask your pharmacist or doctor for
information about MESNEX that is written for health professionals.
For more information, call 1-800-262-3784.
What are the ingredients in MESNEX?
Active ingredient: mesna
Inactive ingredients:
MESNEX injection: edetate disodium, sodium hydroxide, and benzyl alcohol as a preservative.
MESNEX tablets: calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and
titanium dioxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured by:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Baxter and MESNEX are trademarks of Baxter International Inc.
Revised: March 2014
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019884s013lbl.pdf', 'application_number': 19884, 'submission_type': 'SUPPL ', 'submission_number': 13}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019872Orig1s040lbl.pdf', 'application_number': 19872, 'submission_type': 'SUPPL ', 'submission_number': 40}
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Accupril®
(Quinapril Hydrochloride Tablets)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors
can cause injury and even death to the developing fetus. When pregnancy is
detected, ACCUPRIL should be discontinued as soon as possible. See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: Structural Formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin-
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple daily
doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to
proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or
continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and
quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in
those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE
AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension. It may be used alone or in
combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
In using ACCUPRIL, consideration should be given to the fact that another angiotensin-
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
This label may not be the latest approved by FDA.
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renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including ACCUPRIL) may be subject to a variety of adverse reactions, some
of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
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Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
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occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal
morbidity and death when administered to pregnant women. Several dozen cases have been
reported in the world literature. When pregnancy is detected, ACE inhibitors should be
discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure
that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to
ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients
become pregnant, physicians should make every effort to discontinue the use of ACCUPRIL as
soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, ACCUPRIL should be discontinued unless it is considered life
saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as a means of reversing hypotension and/or substituting for disordered renal function. Removal
of ACCUPRIL, which crosses the placenta, from the neonatal circulation is not significantly
accelerated by these means.
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
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PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia and potassium-sparing diuretics: In clinical trials, hyperkalemia (serum
potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
most cases, elevated serum potassium levels were isolated values which resolved despite
continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-
containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (see
PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this mechanism,
it can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors, and they should also be told that these
consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has
been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
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Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Patients should be so advised and told to report
immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS).
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
with the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their
physician that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which could be a sign of neutropenia.
NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride),
potassium supplements, or potassium-containing salt substitutes is indicated, they should be used
with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
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coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
• Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
• The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
• ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
• No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
• Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2,
respectively).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters): See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
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of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
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Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Respiratory: eosinophilic pneumonitis
Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Fetal/Neonatal Morbidity and Mortality
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the
setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered
research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation
and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal
saline solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
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Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (≥65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
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is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
• HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
N0071-0527-23 bottles of 90 tablets
N0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
N0071-0530-23 bottles of 90 tablets
N0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
N0071-0532-23 bottles of 90 tablets
N0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
N0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light.
Rx only Company logo
LAB-0215-5.0
Revised April 2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:46:13.192776
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019885s028lbl.pdf', 'application_number': 19885, 'submission_type': 'SUPPL ', 'submission_number': 28}
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11,808
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Accupril®
(Quinapril Hydrochloride Tablets)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors
can cause injury and even death to the developing fetus. When pregnancy is
detected, ACCUPRIL should be discontinued as soon as possible. See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: structural formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin-
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple
daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound
to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or
continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and
quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in
those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE
AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension. It may be used alone or in
combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In using ACCUPRIL, consideration should be given to the fact that another angiotensin-
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including ACCUPRIL) may be subject to a variety of adverse reactions, some
of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
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Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal
morbidity and death when administered to pregnant women. Several dozen cases have been
reported in the world literature. When pregnancy is detected, ACE inhibitors should be
discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure
that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to
ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients
become pregnant, physicians should make every effort to discontinue the use of ACCUPRIL as
soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, ACCUPRIL should be discontinued unless it is considered life
saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as a means of reversing hypotension and/or substituting for disordered renal function. Removal
of ACCUPRIL, which crosses the placenta, from the neonatal circulation is not significantly
accelerated by these means.
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia and potassium-sparing diuretics: In clinical trials, hyperkalemia (serum
potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
most cases, elevated serum potassium levels were isolated values which resolved despite
continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-
containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (see
PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this
mechanism, it can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors, and they should also be told that these
consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has
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been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Patients should be so advised and told to report
immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS).
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
with the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their
physician that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which could be a sign of neutropenia.
NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride),
potassium supplements, or potassium-containing salt substitutes is indicated, they should be used
with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
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Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
(COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
NSAIDs.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
• Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
• The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
• ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
• No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
• Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2,
respectively).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters): See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
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Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
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General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Respiratory: eosinophilic pneumonitis
Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Fetal/Neonatal Morbidity and Mortality
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
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Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the
setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered
research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation
and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal
saline solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
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Reference ID: 3029113
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Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (≥65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 0071-0527-23 bottles of 90 tablets
NDC 0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
NDC 0071-0530-23 bottles of 90 tablets
NDC 0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
NDC 0071-0532-23 bottles of 90 tablets
NDC 0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
NDC 0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light. company logo
LAB-0215-6.0
Revised August 2011
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Reference ID: 3029113
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019885s033lbl.pdf', 'application_number': 19885, 'submission_type': 'SUPPL ', 'submission_number': 33}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019881s002lbl.pdf', 'application_number': 19881, 'submission_type': 'SUPPL ', 'submission_number': 2}
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Accupril®
(Quinapril Hydrochloride Tablets)
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ACCUPRIL as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: structural formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
1
Reference ID: 3377764
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treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple
daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound
to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous
ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat.
Elimination of quinaprilat may be reduced in elderly patients (65 years) and in those with heart
failure; this reduction is attributable to decrease in renal function (see DOSAGE AND
ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
2
Reference ID: 3377764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes including the class to which this drug
principally belongs. There are no controlled trials demonstrating risk reduction with
ACCUPRIL.
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Reference ID: 3377764
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Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more
than one drug to achieve blood pressure goals. For specific advice on goals and management, see
published guidelines, such as those of the National High Blood Pressure Education Program’s
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
ACCUPRIL may be used alone or in combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
In using ACCUPRIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
4
Reference ID: 3377764
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Do not co-administer aliskiren with ACCUPRIL in patients with diabetes or in patients with
renal impairment (GFR < 60 mL/min/1.73 m2).
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and
polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including
ACCUPRIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk
for angioedema.
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
5
Reference ID: 3377764
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
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Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue ACCUPRIL as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue ACCUPRIL, unless it is considered life-saving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
ACCUPRIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
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Reference ID: 3377764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia and potassium-sparing diuretics: In clinical trials, hyperkalemia (serum
potassium 5.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
most cases, elevated serum potassium levels were isolated values which resolved despite
continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-
containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (see
PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this
mechanism, it can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACCUPRIL during pregnancy. Discuss treatment options with women planning to
become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Patients should be so advised and told to report
immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS).
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
with the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their
physician that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which could be a sign of neutropenia.
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NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride),
potassium supplements, or potassium-containing salt substitutes is indicated, they should be used
with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
(COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
NSAIDs.
Agents that inhibit mTOR or DPP-IV: Patients taking concomitant mTOR inhibitor (e.g.
temsirolimus) therapy may be at increased risk for angioedema.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
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Reference ID: 3377764
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The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS
with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks
of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in
patients on ACCUPRIL and other agents that affect the RAS.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes or in patients with
renal impairment (GFR <60 mL/min/1.73 m2).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2 ,
respectively).
Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
Neonates with a history of in utero exposure to ACCUPRIL:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Removal of ACCUPRIL, which
crosses the placenta, from the neonatal circulation is not significantly accelerated by these
means.
The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
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Reference ID: 3377764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
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Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Respiratory: eosinophilic pneumonitis
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Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting
of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
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Reference ID: 3377764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
NDC 0071-0527-23 bottles of 90 tablets
NDC 0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
NDC 0071-0530-23 bottles of 90 tablets
NDC 0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
NDC 0071-0532-23 bottles of 90 tablets
NDC 0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
NDC 0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light. Pfizer
LAB-0215-9.1
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Reference ID: 3377764
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised September 2013
Reference ID: 3377764
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:13.465789
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019885s038lbl.pdf', 'application_number': 19885, 'submission_type': 'SUPPL ', 'submission_number': 38}
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11,809
|
Accupril®
(Quinapril Hydrochloride Tablets)
WARNING: FETAL TOXICITY
! When pregnancy is detected, discontinue ACCUPRIL as soon as possible.
! Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: structural formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
1
Reference ID: 3192755
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple daily
doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to
proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or
continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and
quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (∀65 years) and in
those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE
AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
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activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (∀65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension. It may be used alone or in
combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
In using ACCUPRIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
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renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and
polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including
ACCUPRIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
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Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
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occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue ACCUPRIL as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue ACCUPRIL, unless it is considered life-saving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
ACCUPRIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
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Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia and potassium-sparing diuretics: In clinical trials, hyperkalemia (serum
potassium ∀5.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
most cases, elevated serum potassium levels were isolated values which resolved despite
continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-
containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (see
PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this mechanism,
it can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACCUPRIL during pregnancy. Discuss treatment options with women planning to
become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Patients should be so advised and told to report
immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS).
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
with the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their
physician that they are taking an ACE inhibitor.
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Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which could be a sign of neutropenia.
NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride),
potassium supplements, or potassium-containing salt substitutes is indicated, they should be used
with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
(COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
NSAIDs.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
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! Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
! The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
! ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
! No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
! Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS
with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks
of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in
patients on ACCUPRIL and other agents that affect the RAS.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes. Avoid use of aliskiren
with ACCUPRIL in patients with renal impairment (GFR <60 ml/min).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2,
respectively).
Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
Neonates with a history of in utero exposure to ACCUPRIL:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Removal of ACCUPRIL, which
crosses the placenta, from the neonatal circulation is not significantly accelerated by these
means.
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The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
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patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
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Respiratory: eosinophilic pneumonitis
Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the
setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered
research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation
and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal
saline solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
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daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (∀65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
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Reference ID: 3192755
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
NDC 0071-0527-23 bottles of 90 tablets
NDC 0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
NDC 0071-0530-23 bottles of 90 tablets
NDC 0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
NDC 0071-0532-23 bottles of 90 tablets
NDC 0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
NDC 0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light. company logo
LAB-0215-7.1
Revised July 2012
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Reference ID: 3192755
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:13.538653
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019885s036lbl.pdf', 'application_number': 19885, 'submission_type': 'SUPPL ', 'submission_number': 36}
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11,812
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Accupril®
(Quinapril Hydrochloride Tablets)
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ACCUPRIL as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: structural formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
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Reference ID: 3818281
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PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple
daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound
to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous
ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat.
Elimination of quinaprilat may be reduced in elderly patients (65 years) and in those with heart
failure; this reduction is attributable to decrease in renal function (see DOSAGE AND
ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
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Reference ID: 3818281
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activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes including the class to which this drug
principally belongs. There are no controlled trials demonstrating risk reduction with
ACCUPRIL.
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Reference ID: 3818281
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Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more
than one drug to achieve blood pressure goals. For specific advice on goals and management, see
published guidelines, such as those of the National High Blood Pressure Education Program’s
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
ACCUPRIL may be used alone or in combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
In using ACCUPRIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
Do not co-administer ACCUPRIL with aliskiren in patients with diabetes.
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Reference ID: 3818281
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and
polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including
ACCUPRIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk
for angioedema.
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
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Reference ID: 3818281
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
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Reference ID: 3818281
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue ACCUPRIL as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue ACCUPRIL, unless it is considered life-saving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
ACCUPRIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
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Reference ID: 3818281
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials, hyperkalemia (serum potassium 5.8 mmol/L) occurred in
approximately 2% of patients receiving ACCUPRIL. In most cases, elevated serum potassium
levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients
discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia
include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise
serum potassium levels. Monitor serum potassium in such patients (see PRECAUTIONS, Drug
Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this
mechanism, it can be corrected by volume expansion.
Information for Patients
Pregnancy: Tell female patients of childbearing age about the consequences of exposure to
ACCUPRIL during pregnancy. Discuss treatment options with women planning to become
pregnant. Ask patients to report pregnancies to their physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Advise patients and tell them to immediately
report any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips,
tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Caution patients that lightheadedness can occur, especially during
the first few days of ACCUPRIL therapy, and that it should be reported to a physician. If actual
syncope occurs, tell patients to temporarily discontinue the drug until they have consulted with
their physician (see WARNINGS).
Caution all patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting
can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the
same consequences of lightheadedness and possible syncope.
Tell patients planning to undergo any surgery and/or anesthesia to inform their physician that
they are taking an ACE inhibitor.
Hyperkalemia: Tell patients not to use potassium supplements or salt substitutes containing
potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Tell patients to promptly report any indication of infection (eg, sore throat, fever)
which could be a sign of neutropenia.
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Reference ID: 3818281
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium:
Coadministration of ACCUPRIL with other drugs that raise serum potassium levels may result in
hyperkalemia. Monitor serum potassium in such patients.
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
(COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
NSAIDs.
Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus)
therapy may be at increased risk for angioedema.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
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No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS
with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks
of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do
not obtain any additional benefit compared to monotherapy. In general, avoid combined use of
RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on
ACCUPRIL and other agents that affect the RAS.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes. Avoid concomitant
use of aliskiren with ACCUPRIL in patients with renal impairment (GFR<60 mL/min/1.73 m2).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2 ,
respectively).
Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
Neonates with a history of in utero exposure to ACCUPRIL:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Removal of ACCUPRIL, which
crosses the placenta, from the neonatal circulation is not significantly accelerated by these
means.
The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
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to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
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Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Respiratory: eosinophilic pneumonitis
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Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting
of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
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Reference ID: 3818281
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patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
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DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
NDC 0071-0527-23 bottles of 90 tablets
NDC 0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
NDC 0071-0530-23 bottles of 90 tablets
NDC 0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
NDC 0071-0532-23 bottles of 90 tablets
NDC 0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
NDC 0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light. company logo
LAB-0215-12.x
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Reference ID: 3818281
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Revised September 2015
Reference ID: 3818281
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:13.595889
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019885s041lbl.pdf', 'application_number': 19885, 'submission_type': 'SUPPL ', 'submission_number': 41}
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11,811
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Accupril®
(Quinapril Hydrochloride Tablets)
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ACCUPRIL as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
ACCUPRIL® (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3
isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 •HCl and
its structural formula is: structural formula
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
aqueous solvents.
ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
Quinapril inhibits the elevation in blood pressure caused by intravenously administered
angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (see
1
Reference ID: 3396368
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PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin
angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
although it was somewhat less effective in blacks (usually a predominantly low renin group) than
in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
quinapril remains to be elucidated.
Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
diminished moderately (approximately 25–30%) when ACCUPRIL tablets are administered
during a high-fat meal. Following absorption, quinapril is deesterified to its major active
metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites.
Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of
quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a
prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and
quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple
daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound
to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine
clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous
ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat.
Elimination of quinaprilat may be reduced in elderly patients (65 years) and in those with heart
failure; this reduction is attributable to decrease in renal function (see DOSAGE AND
ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic
cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and
its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20
mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
angiotensin II levels at 24 hours by doses of 20–80 mg.
Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension
results in a reduction of sitting and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can
occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive
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activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after
dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is
obtained in 1–2 weeks. In multiple-dose studies, 10–80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect
of about 5–11/3–7 mm Hg. The trough effect represents about 50% of the peak effect. While the
dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at
trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood
pressure than once daily dosing with the same total dose. The antihypertensive effect of
ACCUPRIL continues during long-term therapy, with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
glomerular filtration rate, or filtration fraction.
Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effect greater than
that seen with either agent alone.
In patients with hypertension, ACCUPRIL 10–40 mg was similar in effectiveness to captopril,
enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in elderly patients.
Heart Failure: In a placebo-controlled trial involving patients with congestive heart failure
treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
baseline-controlled trials, and such effects appeared to be maintained during chronic oral
quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been
observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as
measured by New York Heart Association (NYHA) classification and Quality of Life and on
symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind,
placebo-controlled study. Favorable effects were maintained for up to two years of open label
therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.
INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes including the class to which this drug
principally belongs. There are no controlled trials demonstrating risk reduction with
ACCUPRIL.
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Reference ID: 3396368
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more
than one drug to achieve blood pressure goals. For specific advice on goals and management, see
published guidelines, such as those of the National High Blood Pressure Education Program’s
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
ACCUPRIL may be used alone or in combination with thiazide diuretics.
Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
conventional therapy including diuretics and/or digitalis.
In using ACCUPRIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease. Available data are insufficient to show that
ACCUPRIL does not have a similar risk (see WARNINGS).
Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have
been reported to have a higher incidence of angioedema compared to non-blacks. It should also
be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is
less in black patients than in non-blacks.
CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes.
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Reference ID: 3396368
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting inhibitors affect the metabolism of eicosanoids and
polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including
ACCUPRIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
patients receiving ACCUPRIL.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in
study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
immediately, the patient treated in accordance with accepted medical care, and carefully
observed until the swelling disappears. In instances where swelling is confined to the face and
lips, the condition generally resolves without treatment; antihistamines may be useful in
relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to
cause airway obstruction, emergency therapy including, but not limited to, subcutaneous
epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see
ADVERSE REACTIONS).
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk
for angioedema.
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema: Patients with a history of angioedema unrelated to
ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
(see also CONTRAINDICATIONS).
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
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Reference ID: 3396368
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Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
receive appropriate medical follow-up.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
hypotension usually is not necessary when dosing instructions are followed. Caution should be
observed when initiating therapy in patients with heart failure (see DOSAGE AND
ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of ACCUPRIL, which usually can be given without
difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
but more frequently in patients with renal impairment, especially if they also have a collagen
vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white
blood cell counts in patients with collagen vascular disease and/or renal disease should be
considered.
Fetal Toxicity
Pregnancy Category D
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Reference ID: 3396368
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Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue ACCUPRIL as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue ACCUPRIL, unless it is considered life-saving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
ACCUPRIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
recommended human dose.
PRECAUTIONS
General
Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine have been observed in some patients
following ACE inhibitor therapy. These increases were almost always reversible upon
discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent preexisting renal vascular
disease have developed increases in blood urea and serum creatinine, usually minor and
transient, especially when ACCUPRIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or
discontinuation of any diuretic and/or ACCUPRIL may be required.
Evaluation of patients with hypertension or heart failure should always include assessment
of renal function (see DOSAGE AND ADMINISTRATION).
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Reference ID: 3396368
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Hyperkalemia and potassium-sparing diuretics: In clinical trials, hyperkalemia (serum
potassium 5.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
most cases, elevated serum potassium levels were isolated values which resolved despite
continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-
containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (see
PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent non-productive cough has been reported with all ACE inhibitors, always resolving
after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this
mechanism, it can be corrected by volume expansion.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACCUPRIL during pregnancy. Discuss treatment options with women planning to
become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. Patients should be so advised and told to report
immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
consulted with their physician (see WARNINGS).
Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS).
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
with the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their
physician that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS).
Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which could be a sign of neutropenia.
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NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
of blood pressure after initiation of therapy with ACCUPRIL. The possibility of hypotensive
effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
increasing salt intake prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
ADMINISTRATION).
Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
ACCUPRIL with potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride),
potassium supplements, or potassium-containing salt substitutes is indicated, they should be used
with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).
Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
magnesium.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
(COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
NSAIDs.
Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus)
therapy may be at increased risk for angioedema.
Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
of single doses of ACCUPRIL.
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The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was
not significantly changed by quinapril coadministration twice-daily.
ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
hydrochlorothiazide were administered concomitantly.
Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
resulted in no significant change in the steady-state pharmacokinetic parameters of
atorvastatin.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS
with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks
of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in
patients on ACCUPRIL and other agents that affect the RAS.
Do not co-administer aliskiren with ACCUPRIL in patients with diabetes. Avoid concomitant
use of aliskiren with ACCUPRIL in patients with renal impairment (GFR <60 mL/min/1.73 m2).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
and 3.8 to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104
weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph
node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat
bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2 ,
respectively).
Nursing Mothers
Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Pediatric Use
Neonates with a history of in utero exposure to ACCUPRIL:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Removal of ACCUPRIL, which
crosses the placenta, from the neonatal circulation is not significantly accelerated by these
means.
The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
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Geriatric Use
Clinical studies of ACCUPRIL did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Elderly patients exhibited increased area under the plasma concentration time curve and peak
levels for quinaprilat compared to values observed in younger patients; this appeared to relate to
decreased renal function rather than to age itself.
ADVERSE REACTIONS
Hypertension
ACCUPRIL has been evaluated for safety in 4960 subjects and patients. Of these, 3203 patients,
including 655 elderly patients, participated in controlled clinical trials. ACCUPRIL has been
evaluated for long-term safety in over 1400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient.
In placebo-controlled trials, discontinuation of therapy because of adverse events was required in
4.7% of patients with hypertension.
Adverse experiences probably or possibly related to therapy or of unknown relationship to
therapy occurring in 1% or more of the 1563 patients in placebo-controlled hypertension trials
who were treated with ACCUPRIL are shown below.
Adverse Events in Placebo-Controlled Trials
Accupril
Placebo
(N=1563)
(N=579)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Headache
5.6 (0.7)
10.9 (0.7)
Dizziness
3.9 (0.8)
2.6 (0.2)
Fatigue
2.6 (0.3)
1.0
Coughing
2.0 (0.5)
0.0
Nausea and/or Vomiting
1.4 (0.3)
1.9 (0.2)
Abdominal Pain
1.0 (0.2)
0.7
Heart Failure
ACCUPRIL has been evaluated for safety in 1222 ACCUPRIL treated patients. Of these, 632
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patients participated in controlled clinical trials. In placebo-controlled trials, discontinuation of
therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
Adverse experiences probably or possibly related or of unknown relationship to therapy
occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials
who were treated with ACCUPRIL are shown below.
Accupril
Placebo
(N=585)
(N=295)
Incidence
Incidence
(Discontinuance)
(Discontinuance)
Dizziness
7.7 (0.7)
5.1 (1.0)
Coughing
4.3 (0.3)
1.4
Fatigue
2.6 (0.2)
1.4
Nausea and/or Vomiting
2.4 (0.2)
0.7
Chest Pain
2.4
1.0
Hypotension
2.9 (0.5)
1.0
Dyspnea
1.9 (0.2)
2.0
Diarrhea
1.7
1.0
Headache
1.7
1.0 (0.3)
Myalgia
1.5
2.0
Rash
1.4 (0.2)
1.0
Back Pain
1.2
0.3
See PRECAUTIONS, Cough.
Hypertension and/or Heart Failure
Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship
to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with CHF or hypertension
treated with ACCUPRIL (with or without concomitant diuretic) in controlled or uncontrolled
trials (N=4847) and less frequent, clinically significant events seen in clinical trials or post-
marketing experience (the rarer events are in italics) include (listed by body system):
General: back pain, malaise, viral infections, anaphylactoid reaction
Cardiovascular: palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial
infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic
hypotension, cardiac rhythm disturbances, cardiogenic shock
Hematology: hemolytic anemia
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage,
pancreatitis, abnormal liver function tests, dyspepsia
Nervous/Psychiatric: somnolence, vertigo, syncope, nervousness, depression, insomnia,
paresthesia
Integumentary: alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis,
photosensitivity reaction, dermatopolymyositis
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Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Respiratory: eosinophilic pneumonitis
Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia
Angioedema
Angioedema has been reported in patients receiving ACCUPRIL (0.1%). Angioedema associated
with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx occurs, treatment with ACCUPRIL should be discontinued and appropriate therapy
instituted immediately. (See WARNINGS.)
Clinical Laboratory Test Findings
Hematology: (See WARNINGS)
Hyperkalemia: (See PRECAUTIONS)
Creatinine and Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in
serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all
patients treated with ACCUPRIL alone. Increases are more likely to occur in patients receiving
concomitant diuretic therapy than in those on ACCUPRIL alone. These increases often remit on
continued therapy. In controlled studies of heart failure, increases in blood urea nitrogen and
serum creatinine were observed in 11% and 8%, respectively, of patients treated with
ACCUPRIL; most often these patients were receiving diuretics with or without digitalis.
OVERDOSAGE
Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats.
No specific information is available on the treatment of overdosage with quinapril. The most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of quinapril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
quinapril overdose.
No data are available to suggest physiological maneuvers (eg, maneuvers to change pH of the
urine) that might accelerate elimination of quinapril and its metabolites.
Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and
quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting
of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Hypertension
Monotherapy: The recommended initial dosage of ACCUPRIL in patients not on diuretics is 10
or 20 mg once daily. Dosage should be adjusted according to blood pressure response measured
at peak (2–6 hours after dosing) and trough (predosing). Generally, dosage adjustments should
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be made at intervals of at least 2 weeks. Most patients have required dosages of 20, 40, or 80
mg/day, given as a single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such
patients an increase in dosage or twice daily administration may be warranted. In general, doses
of 40–80 mg and divided doses give a somewhat greater effect at the end of the dosing interval.
Concomitant Diuretics: If blood pressure is not adequately controlled with ACCUPRIL
monotherapy, a diuretic may be added. In patients who are currently being treated with a
diuretic, symptomatic hypotension occasionally can occur following the initial dose of
ACCUPRIL. To reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued 2 to 3 days prior to beginning therapy with ACCUPRIL (see WARNINGS). Then,
if blood pressure is not controlled with ACCUPRIL alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with
careful medical supervision for several hours and until blood pressure has stabilized.
The dosage should subsequently be titrated (as described above) to the optimal response (see
WARNINGS, PRECAUTIONS, and Drug Interactions).
Renal Impairment: Kinetic data indicate that the apparent elimination half-life of quinaprilat
increases as creatinine clearance decreases. Recommended starting doses, based on clinical and
pharmacokinetic data from patients with renal impairment, are as follows:
Creatinine
Clearance
Maximum Recommended
Initial Dose
>60 mL/min
30–60 mL/min
10–30 mL/min
<10 mL/min
10 mg
5 mg
2.5 mg
Insufficient data for
dosage recommendation
Patients should subsequently have their dosage titrated (as described above) to the optimal
response.
Elderly (65 years): The recommended initial dosage of ACCUPRIL in elderly patients is 10
mg given once daily followed by titration (as described above) to the optimal response.
Heart Failure
ACCUPRIL is indicated as adjunctive therapy when added to conventional therapy including
diuretics and/or digitalis. The recommended starting dose is 5 mg twice daily. This dose may
improve symptoms of heart failure, but increases in exercise duration have generally required
higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated, patients should
then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two
equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see
WARNINGS) prohibit reaching this dose.
Following the initial dose of ACCUPRIL, the patient should be observed under medical
supervision for at least two hours for the presence of hypotension or orthostatis and, if present,
until blood pressure stabilizes. The appearance of hypotension, orthostatis, or azotemia early in
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dose titration should not preclude further careful dose titration. Consideration should be given to
reducing the dose of concomitant diuretics.
DOSE ADJUSTMENTS IN PATIENTS WITH HEART FAILURE AND RENAL
IMPAIRMENT OR HYPONATREMIA
Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function.
In patients with heart failure and renal impairment, the recommended initial dose of ACCUPRIL
is 5 mg in patients with a creatinine clearance above 30 mL/min and 2.5 mg in patients with a
creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in
patients with a creatinine clearance less than 10 mL/min (see DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS, and PRECAUTIONS, Drug Interactions).
If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a twice
daily regimen. In the absence of excessive hypotension or significant deterioration of renal
function, the dose may be increased at weekly intervals based on clinical and hemodynamic
response.
HOW SUPPLIED
ACCUPRIL tablets are supplied as follows:
5-mg tablets: brown, film-coated, elliptical scored tablets, coded “PD 527’’ on one side and “5’’
on the other.
NDC 0071-0527-23 bottles of 90 tablets
NDC 0071-0527-40 10 x 10 unit dose blisters
10-mg tablets: brown, film-coated, triangular tablets, coded “PD 530’’ on one side and “10’’ on
the other.
NDC 0071-0530-23 bottles of 90 tablets
NDC 0071-0530-40 10 x 10 unit dose blisters
20-mg tablets: brown, film-coated, round tablets, coded “PD 532’’ on one side and “20’’ on the
other.
NDC 0071-0532-23 bottles of 90 tablets
NDC 0071-0532-40 10 x 10 unit dose blisters
40-mg tablets: brown, film-coated, elliptical tablets, coded “PD 535’’ on one side and “40’’ on
the other.
NDC 0071-0535-23 bottles of 90 tablets
Dispense in well-closed containers as defined in the USP.
Storage: Store at controlled room temperature 15º–30ºC (59º–86ºF).
Protect from light. company logo
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Reference ID: 3396368
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LAB-0215-10.1
Revised October 2013
Reference ID: 3396368
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2025-02-12T13:46:13.687572
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NDA 19888/S-047
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ZESTORETIC®
(Lisinopril and Hydrochlorothiazide)
USE IN PREGNANCY
When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause
injury and even death to the developing fetus. When pregnancy is detected, Zestoretic should
be discontinued as soon as possible. See WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal
Morbidity and Mortality.
DESCRIPTION
Zestoretic (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme
inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme
inhibitor. It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline
dihydrate. Its empirical formula is C21H31N3O5 . 2H2O and its structural formula is: Structural Formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is
soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1
dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:
H
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight
of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Zestoretic is available for oral use in three tablet combinations of lisinopril with
hydrochlorothiazide: Zestoretic 10-12.5 containing 10 mg lisinopril and 12.5 mg
hydrochlorothiazide; Zestoretic 20-12.5 containing 20 mg lisinopril and 12.5 mg
hydrochlorothiazide; and, Zestoretic 20-25 containing 20 mg lisinopril and 25 mg
hydrochlorothiazide.
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Inactive Ingredients:
10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch,
yellow ferric oxide.
20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, starch.
20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch,
yellow ferric oxide.
CLINICAL PHARMACOLOGY
Lisinopril and Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases
aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the
renin-angiotensin aldosterone axis and tends to reverse the potassium loss associated with the
diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril
and hydrochlorothiazide was approximately additive. The Zestoretic 10-12.5 combination
worked equally well in black and white patients. The Zestoretic 20-12.5 and Zestoretic 20-25
combinations appeared somewhat less effective in black patients, but relatively few black
patients were studied. In most patients, the antihypertensive effect of Zestoretic was sustained
for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of Zestoretic 20-12.5
and Zestoretic 20-25 were similar, suggesting that many patients who respond adequately to the
latter combination may be controlled with Zestoretic 20-12.5 (See DOSAGE AND
ADMINISTRATION).
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the
bioavailability of either drug. The combination tablet is bioequivalent to concomitant
administration of the separate entities.
Lisinopril
Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE
is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor
substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal
cortex. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Removal of angiotensin II negative feedback on renin
secretion leads to increased plasma renin activity. In hypertensive patients with normal renal
function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium
was less than 0.1 mEq/L; however, approximately 15 percent of patients had increases greater
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than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the
same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change
in serum potassium (See PRECAUTIONS).
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril
remains to be elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in
patients with low-renin hypertension. Although lisinopril was antihypertensive in all races
studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller
average response to lisinopril monotherapy than nonblack patients.
Pharmacokinetics and Metabolism:
Following oral administration of lisinopril, peak serum concentrations occur within about 7
hours. Declining serum concentrations exhibit a prolonged terminal phase which does not
contribute to drug accumulation. This terminal phase probably represents saturable binding to
ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum
proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based
on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with
large intersubject variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not
influenced by the presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through
the kidneys, but this decrease becomes clinically important only when the glomerular filtration
rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little
changed. With greater impairment, however, peak and trough lisinopril levels increase, time to
peak concentration increases and time to attain steady state is prolonged. Older patients, on
average, have (approximately doubled) higher blood levels and area under the plasma
concentration time curve (AUC) than younger patients (see DOSAGE AND
ADMINISTRATION). In a multiple dose pharmacokinetic study in elderly versus young
hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased
approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older
patients. Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of
lisinopril in rats do not result in accumulation in any tissues; however, milk of lactating rats
contains radioactivity following administration of 14C lisinopril. By whole body
autoradiography, radioactivity was found in the placenta following administration of labeled
drug to pregnant rats, but none was found in the fetuses.
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Pharmacodynamics:
Administration of lisinopril to patients with hypertension results in a reduction of supine and
standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients (See WARNINGS).
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved
by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks
of therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24
hours, after dosing, although the effect at 24 hours was substantially smaller than the effect six
hours after dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt
withdrawal of lisinopril has not been associated with a rapid increase in blood pressure; nor with
a significant overshoot of pretreatment blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac
output and in heart rate. In a study in nine hypertensive patients, following administration of
lisinopril, there was an increase in mean renal blood flow that was not significant. Data from
several small studies are inconsistent with respect to the effect of lisinopril on glomerular
filtration rate in hypertensive patients with normal renal function, but suggest that changes, if
any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and
effective in controlling blood pressure (See PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually
affect normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular
mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and
chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of
potassium and bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12
hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma
levels have been followed for at least 24 hours, the plasma half-life has been observed to vary
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between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within
24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
INDICATIONS AND USAGE
Zestoretic is indicated for the treatment of hypertension.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND
ADMINISTRATION).
In using Zestoretic, consideration should be given to the fact that an angiotensin-converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal
impairment or collagen vascular disease, and that available data are insufficient to show that
lisinopril does not have a similar risk (See WARNINGS).
In considering the use of Zestoretic, it should be noted that ACE inhibitors have been associated
with a higher rate of angioedema in black than in nonblack patients (see WARNINGS,
Lisinopril).
CONTRAINDICATIONS
Zestoretic is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an angiotensin-converting
enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the
hydrochlorothiazide component, this product is contraindicated in patients with anuria or
hypersensitivity to other sulfonamide-derived drugs.
WARNINGS
Lisinopril
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting
enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including Zestoretic) may be subject to a variety
of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or
larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors,
including lisinopril. This may occur at any time during treatment. ACE inhibitors have been
associated with a higher rate of angioedema in black than in nonblack patients. Zestoretic should
be promptly discontinued and the appropriate therapy and monitoring should be provided until
complete and sustained resolution of signs and symptoms has occurred. Even in those instances
where swelling of only the tongue is involved, without respiratory distress, patients may require
prolonged observation since treatment with antihistamines and corticosteroids may not be
sufficient. Very rarely, fatalities have been reported due to angioedema associated with
laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are
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likely to experience airway obstruction, especially those with a history of airway surgery. Where
there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction,
subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to
ensure a patent airway should be promptly provided (See ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE
and CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Thiazide-containing combination
products are not recommended in patients with severe renal dysfunction. Sudden and potentially
life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-
flux membranes (e.g., AN69®*) and treated concomitantly with an ACE inhibitor. In such
patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid
reactions must be initiated. Symptoms have not been relieved by antihistamines in these
situations. In these patients, consideration should be given to using a different type of dialysis
membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been
reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated
hypertensive patients but is a possible consequence of lisinopril use in salt/volume-depleted
persons such as those treated vigorously with diuretics or patients on dialysis (See
PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).
Syncope has been reported in 0.8 percent of patients receiving Zestoretic. In patients with
hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall
incidence of syncope may be reduced by proper titration of the individual components (See
PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND
ADMINISTRATION).
In patients with severe congestive heart failure, with or without associated renal insufficiency,
excessive hypotension has been observed and may be associated with oliguria and/or progressive
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azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood
pressure in these patients, therapy should be started under very close medical supervision. Such
patients should be followed closely for the first two weeks of treatment and whenever the dose of
lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic
heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a
myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary,
receive an intravenous infusion of normal saline. A transient hypotensive response is not a
contraindication to further doses which usually can be given without difficulty once the blood
pressure has increased after volume expansion.
Leukopenia/Neutropenia/Agranulocytosis: Another angiotensin-converting enzyme inhibitor,
captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in
uncomplicated patients but more frequently in patients with renal impairment, especially if they
also have a collagen vascular disease. Available data from clinical trials of lisinopril are
insufficient to show that lisinopril does not cause agranulocytosis at similar rates. Marketing
experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in
which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood
cell counts in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes)
death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors
who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE
inhibitor and receive appropriate medical follow-up.
Pregnancy
Lisinopril and Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56
times the maximum recommended human dose) in combination with 10 mg/kg/day of
hydrochlorothiazide (2.5 times the maximum recommended human dose). Maternal or fetotoxic
effects were not seen in mice with the combination. In rats decreased maternal weight gain and
decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated
with the decreased fetal weight was a delay in fetal ossification. The decreased fetal weight and
delay in fetal ossification were not seen in saline-supplemented animals given 90/10 mg/kg/day.
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury
and even death to the developing fetus. When pregnancy is detected, Zestoretic should be
discontinued as soon as possible (See Lisinopril, Fetal/Neonatal Morbidity and Mortality below).
Lisinopril
Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity
and death when administered to pregnant women. Several dozen cases have been reported in the
world literature. When pregnancy is detected, ACE inhibitor therapy should be discontinued as
soon as possible.
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In a published retrospective epidemiological study, infants whose mothers had taken an ACE
inhibitor drug during the first trimester of pregnancy appeared to have an increased risk of major
congenital malformations compared with infants whose mothers had not undergone first
trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the
findings of this study have not yet been repeated.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE-inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure
that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to
ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients
become pregnant, physicians should make every effort to discontinue the use of Zestoretic as
soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, Zestoretic should be discontinued unless it is considered
lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or
biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as means of reversing hypotension and/or substituting for disordered renal function. Lisinopril,
which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis
with some clinical benefit, and theoretically may be removed by exchange transfusion, although
there is no experience with the latter procedure.
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a
mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in
rabbits) the maximum recommended human dose.
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Hydrochlorothiazide
Teratogenic Effects: Reproduction studies in the rabbit, the mouse and the rat at doses up to 100
mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the fetus
due to hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses of 4
5.6 mg/kg/day (approximately 1-2 times the usual daily human dose) did not impair fertility or
produce birth abnormalities in the offspring. Thiazides cross the placental barrier and appear in
cord blood.
Nonteratogenic Effects: These may include fetal or neonatal jaundice, thrombocytopenia, and
possibly other adverse reactions have occurred in the adult.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with
impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive
liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic
coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial
asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (See PRECAUTIONS, Drug Interactions,
Lisinopril and Hydrochlorothiazide).
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be
given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the
renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors,
including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with
acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea
nitrogen and serum creatinine may occur. Experience with another angiotensin-converting
enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
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lisinopril and/or diuretic therapy. In such patients renal function should be monitored during the
first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed
increases in blood urea and serum creatinine, usually minor and transient, especially when
lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients
with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the
diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function
(See DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L)
occurred in approximately 1.4 percent of hypertensive patients treated with lisinopril plus
hydrochlorothiazide. In most cases these were isolated values which resolved despite continued
therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant
use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt
substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. Zestoretic should be
used cautiously, if at all, with these agents and with frequent monitoring of serum potassium
(See PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, almost always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory
renin release. If hypotension occurs and is considered to be due to this mechanism, it can be
corrected by volume expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or
receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance,
irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or
after prolonged therapy.
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Interference with adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of
the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Because
lisinopril reduces the production of aldosterone, concomitant therapy with lisinopril attenuates
the diuretic-induced potassium loss (See PRECAUTIONS, Drug Interactions, Agents Increasing
Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment,
except under extraordinary circumstances (as in liver disease or renal disease), chloride
replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is
water restriction, rather than administration of salt except in rare instances when the
hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy
of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become
manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic
therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight
elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked
hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be
discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment
with angiotensin-converting enzyme inhibitors, including Zestoretic. Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more
drug until they have consulted with the prescribing physician.
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Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially
during the first few days of therapy. If actual syncope occurs, the patients should be told to
discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an
excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume
depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should
be advised to consult with their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection
(e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACE inhibitors during pregnancy. These patients should be asked to report
pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with Zestoretic is
warranted. This information is intended to aid in the safe and effective use of this medication. It
is not a disclosure of all possible adverse or intended effects.
Drug Interactions
Lisinopril
Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in
whom diuretic therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with lisinopril. The possibility of
hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or
increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to
continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close
medical supervision after the initial dose for at least two hours and until blood pressure has
stabilized for at least an additional hour (See WARNINGS, and DOSAGE AND
ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril,
an additional antihypertensive effect is usually observed (See DOSAGE AND
ADMINISTRATION).
Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function
who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of
lisinopril may result in a further deterioration of renal function. These effects are usually
reversible. In a study in 36 patients with mild to moderate hypertension where the
antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with
indomethacin, the use of indomethacin was associated with a reduced effect, although the
difference between the two regimens was not significant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19888/S-047
Page 15
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without
evidence of clinically significant adverse interactions. No meaningful clinically important
pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol,
digoxin, or hydrochlorothiazide. The presence of food in the stomach does not alter the
bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-
type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone,
eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt
substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use
of these agents is indicated, because of demonstrated hypokalemia, they should be used with
caution and with frequent monitoring of serum potassium.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with
drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was
usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended
that serum lithium levels be monitored frequently if lisinopril is administered concomitantly with
lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may
be required.
Other antihypertensive drugs - additive effect or potentiation.
Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85
and 43 percent, respectively.
Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not
sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased
responsiveness to the muscle relaxant.
Lithium - should not generally be given with diuretics. Diuretic agents reduce the renal
clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for
lithium preparations before use of such preparations with Zestoretic.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19888/S-047
Page 16
Non-Steroidal Anti-inflammatory Drugs - In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive
effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Zestoretic and non
steroidal anti-inflammatory agents are used concomitantly, the patient should be observed
closely to determine if the desired effect of Zestoretic is obtained.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy including Zestoretic.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril and Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen
test using Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic
activation or in a forward mutation assay using Chinese hamster lung cells. Lisinopril and
hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution rat
hepatocyte assay. In addition, it did not produce increases in chromosomal aberrations in an in
vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks
to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily
human dose, based on body weight and body surface area, respectively). There was no evidence
of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at
doses up to 135 mg/kg/day (about 84 times* the maximum recommended daily human dose).
This dose was 6.8 times the maximum human dose based on body surface area in mice.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic
activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte
assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro
test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with
up to 300 mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily
human dose based on mg/kg and mg/m2, respectively.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male
and female rats (at doses of up to approximately 100 mg/kg/day). These doses are 150 times and
12 times for mice and 25 times and 4 times for rats the maximum human daily dose based on
mg/kg and mg/m2, respectively. The NTP, however, found equivocal evidence for
hepatocarcinogenicity in male mice.
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NDA 19888/S-047
Page 17
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse
germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila
sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO
Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity)
assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the
Aspergillus nidulans nondisjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg,
respectively, prior to conception and throughout gestation. In mice this dose is 25 times and
2 times the maximum daily human dose based on mg/kg and mg/m2, respectively. In rats this
dose is 1 times and 0.2 times the maximum daily human dose based on mg/kg and mg/m2,
respectively.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See
WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats
contains radioactivity following administration of 14C lisinopril. In another study, lisinopril was
present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human
milk. Because of the potential for serious adverse reactions in nursing infants from ACE
inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing
and/or discontinue Zestoretic, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Zestoretic did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection. Evaluation
of the hypertensive patient should always include assessment of renal function.
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NDA 19888/S-047
Page 18
ADVERSE REACTIONS
Zestoretic has been evaluated for safety in 930 patients including 100 patients treated for 50
weeks or more.
In clinical trials with Zestoretic no adverse experiences peculiar to this combination drug have
been observed. Adverse experiences that have occurred have been limited to those that have
been previously reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label
extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5%),
headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were
more common than in placebo-treated patients. Generally, adverse experiences were mild and
transient in nature, but see WARNINGS regarding angioedema and excessive hypotension or
syncope. Discontinuation of therapy due to adverse effects was required in 4.4% of patients
principally because of dizziness, cough, fatigue and muscle cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies
Lisinopril and
Hydrochlorothiazide
(n=930)
Incidence
(discontinuation)
Placebo
(n=207)
Incidence
Dizziness
7.5
(0.8)
1.9
Headache
5.2
(0.3)
1.9
Cough
3.9
(0.6)
1.0
Fatigue
3.7
(0.4)
1.0
Orthostatic Effects
3.2
(0.1)
1.0
Diarrhea
2.5
(0.2)
2.4
Nausea
2.2
(0.1)
2.4
Upper Respiratory Infection
2.2
(0.0)
0.0
Muscle Cramps
2.0
(0.4)
0.5
Asthenia
1.8
(0.2)
1.0
Paresthesia
1.5
(0.1)
0.0
Hypotension
1.4
(0.3)
0.5
Vomiting
1.4
(0.1)
0.5
Dyspepsia
1.3
(0.0)
0.0
Rash
1.2
(0.1)
0.5
Impotence
1.2
(0.3)
0.0
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NDA 19888/S-047
Page 19
Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer,
serious, possibly drug-related events reported in marketing experience are listed below:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus
infection. Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal
cramps, dry mouth, constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee
pain, back strain, myalgia, foot pain. Nervous/Psychiatric: Decreased libido, vertigo,
depression, somnolence. Respiratory: Common cold, nasal congestion, influenza, bronchitis,
pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal
discomfort. Skin: Flushing, pruritus, skin inflammation, diaphoresis, cutaneous
pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract
infection.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been
reported (See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows:
hypotension (1.4%), orthostatic hypotension (0.5%), other orthostatic effects (3.2%). In addition
syncope occurred in 0.8% of patients (See WARNINGS).
Cough: See PRECAUTIONS - Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: (See PRECAUTIONS.)
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum
creatinine were observed in patients with essential hypertension treated with ZESTORETIC.
More marked increases have also been reported and were more likely to occur in patients with
renal artery stenosis. (See PRECAUTIONS.)
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See
PRECAUTIONS).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases
of approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive
patients treated with ZESTORETIC but were rarely of clinical importance unless another cause
of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have
occurred. (See WARNINGS, Hepatic Failure.)
Other adverse reactions that have been reported with the individual components are listed below:
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NDA 19888/S-047
Page 20
Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with
Zestoretic. In addition, and since lisinopril has been marketed, the following adverse reactions
have been reported with lisinopril and should be considered potential adverse reactions for
Zestoretic: Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid
Reactions During Membrane Exposure), malaise, edema, facial edema, pain, pelvic pain, flank
pain, chills; Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident,
possibly secondary to excessive hypotension in high risk patients (see WARNINGS,
Hypotension), pulmonary embolism and infarction, worsening of heart failure, arrhythmias
(including tachycardia, ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia,
and premature ventricular contractions), angina pectoris, transient ischemic attacks, paroxysmal
nocturnal dyspnea, decreased blood pressure, peripheral edema, vasculitis; Digestive:
Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic
Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus;
inappropriate antidiuretic hormone secretion; Hematologic: Rare cases of bone marrow
depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been
reported in which a causal relationship to lisinopril can not be excluded; Metabolic: Gout,
weight loss, dehydration, fluid overload, weight gain;
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain,
lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm,
hypersomnia, irritability; mood alterations (including depressive symptoms); Respiratory:
Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm,
asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful
respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound
abnormalities; Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin
infections, pemphigus, erythema, rare cases of other severe skin reactions, including toxic
epidermal necrolysis and Stevens-Johnson Syndrome (causal relationship has not been
established); Special Senses: Visual loss, diplopia, photophobia, taste alteration, olfactory
disturbance; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive azotemia,
renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),
pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis,
eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations
may occur alone or in combination with these symptoms.
Fetal/Neonatal Morbidity and Mortality
See WARNINGS - Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.
Hydrochlorothiazide - Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation,
cramping, jaundice (intrahepatic cholestatic jaundice (See WARNINGS, Hepatic Failure),
pancreatitis, sialoadenitis, constipation; Hematologic: Leukopenia, agranulocytosis,
thrombocytopenia, aplastic anemia, hemolytic anemia; Musculoskeletal: Muscle spasm;
Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial
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NDA 19888/S-047
Page 21
nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson Syndrome,
exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses:
Xanthopsia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis
(vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary
edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with Zestoretic. Treatment
is symptomatic and supportive. Therapy with Zestoretic should be discontinued and the patient
observed closely. Suggested measures include induction of emesis and/or gastric lavage, and
correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Lisinopril
Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of
20 mice receiving the same dose. The most likely manifestation of overdosage would be
hypotension, for which the usual treatment would be intravenous infusion of normal saline
solution.
Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During
Membrane Exposure).
Hydrochlorothiazide
Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most
common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia,
hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has
also been administered, hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80
mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 - 50 mg per day. In
clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of
10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates
generally increased with increasing dose of either component.
The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of
dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily
hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more
common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide
may be associated with either or both dose-independent or dose-dependent side effects, but
addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy
only after a patient has failed to achieve the desired effect with monotherapy.
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NDA 19888/S-047
Page 22
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately
controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to
lisinopril/HCTZ 10/12.5 or lisinopril/HCTZ 20/12.5, depending on current monotherapy dose.
Further increases of either or both components should depend on clinical response with blood
pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive
effect at that time. The hydrochlorothiazide dose should generally not be increased until 2-3
weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of
lisinopril. Patients whose blood pressures are adequately controlled with 25 mg of daily
hydrochlorothiazide, but who experience significant potassium loss with this regimen may
achieve similar or greater blood-pressure control without electrolyte disturbance if they are
switched to lisinopril/HCTZ 10/12.5.
In patients who are currently being treated with a diuretic, symptomatic hypotension
occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible,
be discontinued for two to three days before beginning therapy with lisinopril to reduce the
likelihood of hypotension. (See WARNINGS.) If the patient's blood pressure is not controlled
with lisinopril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under
medical supervision for at least two hours and until blood pressure has stabilized for at least an
additional hour (See WARNINGS and PRECAUTIONS, Drug Interactions).
Concomitant administration of Zestoretic with potassium supplements, potassium salt substitutes
or potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).
Replacement Therapy: The combination may be substituted for the titrated individual
components.
Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of
renal function as long as the patient's creatinine clearance is >30 mL/min/1.7m2 (serum
creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment,
loop diuretics are preferred to thiazides, so lisinopril/HCTZ is not recommended (see
WARNINGS, Anaphylactoid Reactions During Membrane Exposure).
HOW SUPPLIED
Zestoretic 10-12.5 Tablets (NDC 0310-0141) Peach, round, biconvex, uncoated tablets
identified with "141" debossed on one side and "ZESTORETIC" on the other side are supplied in
bottles of 100 tablets.
Zestoretic 20-12.5 Tablets (NDC 0310-0142) White, round, biconvex, uncoated tablets identified
with "142" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles
of 100 tablets.
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NDA 19888/S-047
Page 23
Zestoretic 20-25 Tablets (NDC 0310-0145) Peach, round, biconvex, uncoated tablets identified
with “145” debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of
100 tablets.
Storage
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from excessive
light and humidity.
Zestoretic is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2009
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca UK Limited
Macclesfield, UK
Made in the United Kingdom
Rev. 05/09
SIC 35366-00 01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:13.872284
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019888s047lbl.pdf', 'application_number': 19888, 'submission_type': 'SUPPL ', 'submission_number': 47}
|
11,813
|
Synarel®
(nafarelin acetate)
nasal solution
CENTRAL PRECOCIOUS PUBERTY
(FOR ENDOMETRIOSIS, SEE REVERSE SIDE)
PHYSICIAN LABELING
DESCRIPTION
SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to
the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution,
is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl
L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate.
Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing
hormone (GnRH).
Nafarelin acetate has the following chemical structure: structural formula
SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as
nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium
hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for SYNAREL, each actuation of the unit delivers
approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The
contents of one spray bottle are intended to deliver at least 60 sprays.
CLINICAL PHARMACOLOGY
Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone
(GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary
gonadotropins, LH and FSH, resulting in a temporary increase of gonadal
steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland.
Twice daily administration leads to decreased secretion of gonadal steroids by about 4
weeks; consequently, tissues and functions that depend on gonadal steroids for their
Reference ID: 2886729
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maintenance become quiescent.
In children, nafarelin acetate was rapidly absorbed into the systemic circulation after
intranasal administration. Maximum serum concentrations (measured by RIA) were
achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the
observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg
base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of
nafarelin following intranasal administration of a 400 µg dose was approximately 2.5
hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin
will be in children given a dose above 600 µg.
In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation
after intranasal administration. Maximum serum concentrations (measured by RIA) were
achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the
observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas
following a single dose of 400 µg base, the observed average peak concentration was 1.8
ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8%
(range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal
administration was approximately 3 hours. About 80% of nafarelin acetate was bound to
plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of
SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of
the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose
proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose
was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the
administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of
the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of
which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-GIy-NH2(5-10). The activity of
the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics
of the drug in hepatically- and renally- impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
When used regularly in girls and boys with central precocious puberty (CPP) at the
recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to
prepubertal levels, affects a corresponding arrest of secondary sexual development, and
slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal
bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter,
menstruation should cease.
In clinical studies the peak response of LH to GnRH stimulation was reduced from a
pubertal response to a prepubertal response (< 15 mlU/mL) within one month of
treatment.
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Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in
most children within the first year of treatment to values of 5 to 6 cm/year or less.
Children with CPP are frequently taller than their chronological age peers; height for
chronological age approaches normal in most children during the second or third year of
treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone
age divided by change in chronological age) is usually abnormal (greater than 1) in
children with CPP; in most children, bone age velocity approaches normal (1) during the
first year of treatment. This results in a narrowing of the gap between bone age and
chronological age, usually by the second or third year of treatment. The mean predicted
adult height increases.
In clinical trials, breast development was arrested or regressed in 82% of girls, and
genital development was arrested or regressed in 100% of boys. Because pubic hair
growth is largely controlled by adrenal androgens, which are unaffected by nafarelin,
pubic hair development was arrested or regressed only in 54% of girls and boys.
Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all
children with CPP for whom one-year posttreatment follow-up is available (n=69). This
demonstration consisted of the appearance or return of menses, the return of pubertal
gonadotropin and gonadal sex steroid levels, and/or the advancement of secondary sexual
development. Semen analysis was normal in the two ejaculated specimens obtained thus
far from boys who have been taken off therapy to resume puberty. Fertility has not been
documented by pregnancies and the effect of long-term use of the drug on fertility is not
known.
INDICATIONS AND USAGE
FOR CENTRAL PRECOCIOUS PUBERTY
(For Endometriosis, See Reverse Side)
SYNAREL is indicated for treatment of central precocious puberty (CPP)
(gonadotropin-dependent precocious puberty) in children of both sexes.
The diagnosis of central precocious puberty (CPP) is suspected when premature
development of secondary sexual characteristics occurs at or before the age of 8 years in
girls and 9 years in boys, and is accompanied by significant advancement of bone age
and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal
gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH.
Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the
latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning
of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical
changes associated with increased intracranial pressure. Other causes of sexual precocity,
such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other
autonomous feminizing or masculinizing disorders must be excluded by proper clinical
hormonal and diagnostic imaging examinations.
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CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
SYNAREL;
2. Undiagnosed abnormal vaginal bleeding;
3. Use in pregnancy or in women who may become pregnant while receiving the drug.
SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rats, but not in mice or rabbits after administration of
SYNAREL during the period of organogenesis. There was a dose-related increase in fetal
mortality and a decrease in fetal weight in rats (see Pregnancy Section). The effects on
rat fetal mortality are expected consequences of the alterations in hormonal levels
brought about by the drug. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, she should be apprised of the potential hazard to the
fetus;
4. Use in women who are breast-feeding (see Nursing Mothers Section).
WARNINGS
The diagnosis of central precocious puberty (CPP) must be established before
treatment is initiated. Regular monitoring of CPP patients is needed to assess both
patient response as well as compliance. This is particularly important during the first 6 to
8 weeks of treatment to assure that suppression of pituitary-gonadal function is rapid.
Testing may include LH response to GnRH stimulation and circulating gonadal sex
steroid levels. Assessment of growth velocity and bone age velocity should begin within
3 to 6 months of treatment initiation.
Some patients may not show suppression of the pituitary-gonadal axis by clinical and/or
biochemical parameters. This may be due to lack of compliance with the recommended
treatment regimen and may be rectified by recommending that the dosing be done by
caregivers. If compliance problems are excluded, the possibility of gonadotropin
independent sexual precocity should be reconsidered and appropriate examinations
should be conducted. If compliance problems are excluded and if gonadotropin
independent sexual precocity is not present, the dose of SYNAREL may be increased to
1800 µg/day administered as 600 µg tid.
PRECAUTIONS
General
As with other drugs that stimulate the release of gonadotropins or that induce ovulation,
in adult women with endometriosis ovarian cysts have been reported to occur in the first
two months of therapy with SYNAREL. Many, but not all, of these events occurred in
women with polycystic ovarian disease. These cystic enlargements may resolve
spontaneously, generally by about four to six weeks of therapy, but in some cases may
require discontinuation of drug and/or surgical intervention. The relevance, if any, of
such events in children is unknown.
Information for Patients, Patients’ Parents or Guardians
An information pamphlet for patients is included with the product. Patients and their
caregivers should be aware of the following information:
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1. Reversibility of the suppressive effects of nafarelin has been demonstrated by the
appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex
steroid levels, and/or by advancement of secondary sexual development. Semen analysis
was normal in the two ejaculated specimens obtained thus far from boys who have been
taken off therapy to resume puberty. Fertility has not been documented by pregnancies
and the effect of long-term use of the drug on fertility is not known.
2. Patients and their caregivers should be adequately counseled to assure full compliance;
irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.
3. During the first month of treatment with SYNAREL, some signs of puberty, e.g.,
vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of
the drug. Such changes should resolve soon after the first month. lf such resolution does
not occur within the first two months of treatment, this may be due to lack of compliance
or the presence of gonadotropin independent sexual precocity. If both possibilities are
definitively excluded, the dose of SYNAREL may be increased to 1800 µg/day
administered as 600 µg tid.
4. Patients with intercurrent rhinitis should consult their physician for the use of a topical
nasal decongestant. If the use of a topical nasal decongestant is required during treatment
with SYNAREL, the decongestant should not be used until at least 2 hours following
dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, because this may impair drug absorption.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with
SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound
to plasma proteins at 4°C, drug interactions would not be expected to occur.
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies of
nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18
months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560
times the maximum recommended human intranasal dose, respectively). These multiples
of the human dose are based on the relative bioavailability of the drug by the two routes
of administration. As seen with other GnRH agonists, nafarelin acetate given to
laboratory rodents at high doses for prolonged periods induced proliferative responses
(hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase
in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a
dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas
in both sexes, and in benign testicular and ovarian tumors in the treated groups. There
was a dose-related increase in benign adrenal medullary tumors in treated female rats. In
mice, there was a dose-related increase in Harderian gland tumors in males and an
increase in pituitary adenomas in high-dose females. No metastases of these tumors were
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observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal
stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and
mammalian systems. These studies provided no evidence of mutagenic potential.
Reproduction studies in male and female rats have shown full reversibility of fertility
suppression when drug treatment was discontinued after continuous administration for up
to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive
performance of mature animals has not been investigated.
Pregnancy, Teratogenic Effects
Pregnancy Category X. See ‘CONTRAINDICATIONS.’ Intramuscular SYNAREL was
administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day
(about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on
the relative bioavailability by the two routes of administration). An increase in major fetal
abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at
the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and
0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after
administration during the period of organogenesis. In rats and rabbits, there was a dose-
related increase in fetal mortality and a decrease in fetal weight with the highest dose.
Nursing Mothers
It is not known whether SYNAREL is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of SYNAREL on lactation and/or the
breastfed child have not been determined, SYNAREL should not be used by nursing
mothers.
ADVERSE REACTIONS
In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug
sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus.
In these 155 patients treated for an average of 41 months and as long as 80 months (6.7
years), adverse events most frequently reported (>3% of patients) consisted largely of
episodes occurring during the first 6 weeks of treatment as a result of the transient
stimulatory action of nafarelin upon the pituitary-gonadal axis:
acne (10%)
transient breast enlargement (8%)
vaginal bleeding (8%)
emotional lability (6%)
transient increase in pubic hair (5%)
body odor (4%)
seborrhea (3%)
Hot flashes, common in adult women treated for endometriosis, occurred in only 3% of
treated children and were transient. Other adverse events thought to be drug-related, and
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occurring in > 3% of patients were rhinitis (5%) and white or brownish vaginal discharge
(3%). Approximately 3% of patients withdrew from clinical trials due to adverse events.
In one male patient with concomitant congenital adrenal hyperplasia, and who had
discontinued treatment 8 months previously to resume puberty, adrenal rest tumors were
found in the left testis. Relationship to SYNAREL is unlikely.
Regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or
computer assisted tomography (CT) of children during long-term nafarelin therapy as
well as during the post-treatment period has occasionally revealed changes in the shape
and size of the pituitary gland. These changes include asymmetry and enlargement of the
pituitary gland, and a pituitary microadenoma has been suspected in a few children. The
relationship of these findings to SYNAREL is not known.
Post-Marketing
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy
(a clinical syndrome secondary to infarction of the pituitary gland) have been reported
after the administration of gonadotropin-releasing hormone agonists. In a majority of
these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy
cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.
Immediate medical attention has been required.
OVERDOSAGE
In experimental animals, a single subcutaneous administration of up to 60 times the
recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no
adverse effects. At present, there is no clinical evidence of adverse effects following
overdosage of GnRH analogs.
Based on studies in monkeys, SYNAREL is not absorbed after oral administration.
DOSAGE AND ADMINISTRATION
For the treatment of central precocious puberty (CPP), the recommended daily dose of
SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate
suppression cannot be achieved at 1600 µg/day.
The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4
sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per
day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three
times a day, a total of 9 sprays per day. The patient’s head should be tilted back slightly,
and 30 seconds should elapse between sprays.
If the prescribed therapy has been well tolerated by the patient, treatment of CPP with
SYNAREL should continue until resumption of puberty is desired.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
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systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, because this may impair drug absorption.
At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays).
If the daily dose is increased, increase the supply to the patient to ensure uninterrupted
treatment for the duration of therapy.
HOW SUPPLIED
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate)
Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump
that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient
instructions are also included.
Store upright at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP
Controlled Room Temperature]. Protect from light.
Rx only
Revised: December 2010 company logo
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Synarel®
(nafarelin acetate)
nasal solution
ENDOMETRIOSIS
(FOR CENTRAL PRECOCIOUS PUBERTY,
SEE REVERSE SIDE)
PHYSICIAN LABELING
DESCRIPTION
SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to
the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution,
is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl
L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate.
Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing
hormone (GnRH).
Nafarelin acetate has the following chemical structure: structural formula
SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as
nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium
hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for SYNAREL, each actuation of the unit delivers
approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The
contents of one spray bottle are intended to deliver at least 60 sprays.
CLINICAL PHARMACOLOGY
Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone
(GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary
gonadotropins, LH and FSH, resulting in a temporary increase of ovarian steroidogenesis.
Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily
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administration leads to decreased secretion of gonadal steroids by about 4 weeks;
consequently, tissues and functions that depend on gonadal steroids for their maintenance
become quiescent.
Nafarelin acetate is rapidly absorbed into the systemic circulation after intranasal
administration. Maximum serum concentrations (measured by RIA) were achieved
between 10 and 40 minutes. Following a single dose of 200 µg base, the observed
average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a
single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL
(range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to
5.6%). The average serum half-life of nafarelin following intranasal administration is
approximately 3 hours. About 80% of nafarelin acetate is bound to plasma proteins at
4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy
women for 22 days did not lead to significant accumulation of the drug. Based on the
mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the
two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose
was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the
administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of
the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of
which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-GIy-NH2(5-10). The activity of
the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics
of the drug in hepatically- and renally-impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing of SYNAREL.
In controlled clinical studies, SYNAREL at doses of 400 and 800 µg/day for 6 months
was shown to be comparable to danazol, 800 mg/day, in relieving the clinical symptoms
of endometriosis (pelvic pain, dysmenorrhea, and dyspareunia) and in reducing the size
of endometrial implants as determined by laparoscopy. The clinical significance of a
decrease in endometriotic lesions is not known at this time and, in addition, laparoscopic
staging of endometriosis does not necessarily correlate with severity of symptoms.
In a single controlled clinical trial, intranasal SYNAREL (nafarelin acetate) at a dose of
400 µg per day was shown to be clinically comparable to intramuscular leuprolide depot,
3.75 mg monthly, for the treatment of the symptoms (dysmenorrhea, dyspareunia and
pelvic pain) associated with endometriosis.
SYNAREL 400 µg daily induced amenorrhea in approximately 65%, 80%, and 90% of
the patients after 60, 90, and 120 days, respectively. In the first, second, and third post
treatment months, normal menstrual cycles resumed in 4%, 82%, and 100%, respectively,
of those patients who did not become pregnant.
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At the end of treatment, 60% of patients who received SYNAREL, 400 µg/day, were
symptom free, 32% had mild symptoms, 7% had moderate symptoms, and 1% had severe
symptoms. Of the 60% of patients who had complete relief of symptoms at the end of
treatment, 17% had moderate symptoms 6 months after treatment was discontinued, 33%
had mild symptoms, 50% remained symptom free, and no patient had severe symptoms.
During the first two months use of SYNAREL, some women experience vaginal bleeding
of variable duration and intensity. In all likelihood, this bleeding represents estrogen
withdrawal bleeding and is expected to stop spontaneously. If vaginal bleeding continues,
the possibility of lack of compliance with the dosing regimen should be considered. If the
patient is complying carefully with the regimen, an increase in dose to 400 µg twice a day
should be considered.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use
of SYNAREL.
INDICATIONS AND USAGE FOR ENDOMETRIOSIS
(For Central Precocious Puberty, See Reverse Side)
SYNAREL is indicated for management of endometriosis, including pain relief and
reduction of endometriotic lesions. Experience with SYNAREL for the management of
endometriosis has been limited to women 18 years of age and older treated for 6 months.
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
SYNAREL;
2. Undiagnosed abnormal vaginal bleeding;
3. Use in pregnancy or in women who may become pregnant while receiving the drug.
SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rats, but not in mice or rabbits after administration of
SYNAREL during the period of organogenesis. There was a dose-related increase in
fetal mortality and a decrease in fetal weight in rats (see Pregnancy Section). The
effects on rat fetal mortality are expected consequences of the alterations in hormonal
levels brought about by the drug. If this drug is used during pregnancy or if the patient
becomes pregnant while taking this drug, she should be apprised of the potential
hazard to the fetus;
4. Use in women who are breast-feeding (see Nursing Mothers Section).
WARNINGS
Safe use of nafarelin acetate in pregnancy has not been established clinically. Before
starting treatment with SYNAREL, pregnancy must be excluded.
When used regularly at the recommended dose, SYNAREL usually inhibits ovulation and
stops menstruation. Contraception is not insured, however, by taking SYNAREL,
particularly if patients miss successive doses. Therefore, patients should use nonhormonal
methods of contraception. Patients should be advised to see their physician if they believe
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they may be pregnant. If a patient becomes pregnant during treatment, the drug must be
discontinued and the patient must be apprised of the potential risk to the fetus.
PRECAUTIONS
General
As with other drugs that stimulate the release of gonadotropins or that induce ovulation,
ovarian cysts have been reported to occur in the first two months of therapy with
SYNAREL. Many, but not all, of these events occurred in patients with polycystic
ovarian disease. These cystic enlargements may resolve spontaneously, generally by
about four to six weeks of therapy, but in some cases may require discontinuation of drug
and/or surgical intervention.
Information for Patients
An information pamphlet for patients is included with the product. Patients should be
aware of the following information:
1. Because menstruation should stop with effective doses of SYNAREL, the patient
should notify her physician if regular menstruation persists. The cause of vaginal
spotting, bleeding or menstruation could be noncompliance with the treatment
regimen, or it could be that a higher dose of the drug is required to achieve
amenorrhea. The patient should be questioned regarding her compliance. If she is
careful and compliant, and menstruation persists to the second month, consideration
should be given to doubling the dose of SYNAREL. If the patient has missed several
doses, she should be counseled on the importance of taking SYNAREL regularly as
prescribed.
2. Patients should not use SYNAREL if they are pregnant, breastfeeding, have
undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in
SYNAREL.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a
nonhormonal method of contraception should be used during treatment. Patients
should be advised that if they miss successive doses of SYNAREL, breakthrough
bleeding or ovulation may occur with the potential for conception. If a patient
becomes pregnant during treatment, she should discontinue treatment and consult her
physician.
4. Those adverse events occurring most frequently in clinical studies with SYNAREL are
associated with hypoestrogenism; the most frequently reported are hot flashes,
headaches, emotional lability, decreased libido, vaginal dryness, acne, myalgia, and
reduction in breast size. Estrogen levels returned to normal after treatment was
discontinued. Nasal irritation occurred in about 10% of all patients who used intranasal
nafarelin.
5. The induced hypoestrogenic state results in a small loss in bone density over the
course of treatment, some of which may not be reversible. During one six-month
treatment period, this bone loss should not be important. In patients with major risk
factors for decreased bone mineral content such as chronic alcohol and/or tobacco use,
strong family history of osteoporosis, or chronic use of drugs that can reduce bone
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mass such as anticonvulsants or corticosteroids, therapy with SYNAREL may pose an
additional risk. In these patients the risks and benefits must be weighed carefully
before therapy with SYNAREL is instituted. Repeated courses of treatment with
gonadotropin releasing hormone analogs are not advisable in patients with major risk
factors for loss of bone mineral content.
6. Patients with intercurrent rhinitis should consult their physician for the use of a topical
nasal decongestant. If the use of a topical nasal decongestant is required during
treatment with SYNAREL, the decongestant should not be used until at least 2 hours
following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, because this may impair drug absorption.
7. Retreatment cannot be recommended because safety data beyond 6 months are not
available.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with
SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound
to plasma proteins at 4°C, drug interactions would not be expected to occur.
Drug/Laboratory Test Interactions
Administration of SYNAREL in therapeutic doses results in suppression of the pituitary-
gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is
discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions
conducted during treatment and up to 4 to 8 weeks after discontinuation of therapy with
SYNAREL may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to
100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular
doses (up to 110 times and 560 times the maximum recommended human intranasal dose,
respectively). These multiples of the human dose are based on the relative bioavailability
of the drug by the two routes of administration. As seen with other GnRH agonists,
nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced
proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months,
there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-
dose female rats and a dose-related increase in male rats. There was an increase in
pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors
in the treated groups. There was a dose-related increase in benign adrenal medullary
tumors in treated female rats. In mice, there was a dose-related increase in Harderian
gland tumors in males and an increase in pituitary adenomas in high-dose females. No
metastases of these tumors were observed. It is known that tumorigenicity in rodents is
particularly sensitive to hormonal stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and
mammalian systems. These studies provided no evidence of mutagenic potential.
Reference ID: 2886729
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Reproduction studies in male and female rats have shown full reversibility of fertility
suppression when drug treatment was discontinued after continuous administration for up
to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive
performance of mature animals has not been investigated.
Pregnancy, Teratogenic Effects
Pregnancy Category X. See ‘CONTRAINDICATIONS.’ Intramuscular SYNAREL was
administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day
(about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on
the relative bioavailability by the two routes of administration). An increase in major fetal
abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at
the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and
0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after
administration during the period of organogenesis. In rats and rabbits, there was a dose-
related increase in fetal mortality and a decrease in fetal weight with the highest dose.
Nursing Mothers
It is not known whether SYNAREL is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of SYNAREL on lactation and/or the
breastfed child have not been determined, SYNAREL should not be used by nursing
mothers.
Pediatric Use
Safety and effectiveness of SYNAREL for endometriosis in patients younger than 18
years have not been established.
ADVERSE REACTIONS
Clinical Studies
In formal clinical trials of 1509 healthy adult patients, symptoms suggestive of drug
sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus occurred in
3 patients (approximately 0.2%).
As would be expected with a drug which lowers serum estradiol levels, the most
frequently reported adverse reactions were those related to hypoestrogenism.
In controlled studies comparing SYNAREL (400 µg/day) and danazol (600 or 800
mg/day), adverse reactions most frequently reported and thought to be drug-related are
shown in the figure below:
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graph
In addition, less than 1% of patients experienced paresthesia, palpitations, chloasma,
maculopapular rash, eye pain, asthenia, lactation, breast engorgement, and arthralgia.
Changes in Bone Density
After six months of treatment with SYNAREL, vertebral trabecular bone density and
total vertebral bone mass, measured by quantitative computed tomography (QCT),
decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment
levels. There was partial recovery of bone density in the post-treatment period; the
average trabecular bone density and total bone mass were 4.9% and 3.3% less than the
pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon
absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment.
After six months treatment with SYNAREL, bone mass as measured by dual x-ray bone
densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by
DEXA six months after completion of treatment, was 1.4% below pretreatment. There
was little, if any, decrease in the mineral content in compact bone of the distal radius and
second metacarpal. Use of SYNAREL for longer than the recommended six months or in
the presence of other known risk factors for decreased bone mineral content may cause
additional bone loss.
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Changes in Laboratory Values During Treatment
Plasma enzymes. During clinical trials with SYNAREL, regular laboratory monitoring
revealed that SGOT and SGPT levels were more than twice the upper limit of normal in
only one patient each. There was no other clinical or laboratory evidence of abnormal
liver function and levels returned to normal in both patients after treatment was stopped.
Lipids. At enrollment, 9% of the patients in the group taking SYNAREL 400 µg/day and
2% of the patients in the danazol group had total cholesterol values above 250 mg/dL.
These patients also had cholesterol values above 250 mg/dL at the end of treatment.
Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in
the group treated with SYNAREL and 18% in the danazol group, had post-treatment
values above 250 mg/dL.
The mean (± SEM) pretreatment values for total cholesterol from all patients were 191.8
(4.3) mg/dL in the group treated with SYNAREL and 193.1 (4.6) mg/dL in the danazol
group. At the end of treatment, the mean values for total cholesterol from all patients
were 204.5 (4.8) mg/dL in the group treated with SYNAREL and 207.7 (5.1) mg/dL in
the danazol group. These increases from the pretreatment values were statistically
significant (p<0.05) in both groups.
Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients
who received SYNAREL and in 7% of the patients who received danazol.
At the end of treatment, no patients receiving SYNAREL had abnormally low HDL
cholesterol fractions (less than 30 mg/dL) compared with 43% of patients receiving
danazol. None of the patients receiving SYNAREL had abnormally high LDL cholesterol
fractions (greater than 190 mg/dL) compared with 15% of those receiving danazol. There
was no increase in the LDL/HDL ratio in patients receiving SYNAREL, but there was
approximately a 2-fold increase in the LDL/HDL ratio in patients receiving danazol.
Other changes. In comparative studies, the following changes were seen in
approximately 10% to 15% of patients. Treatment with SYNAREL was associated with
elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium
and WBC counts. Danazol therapy was associated with an increase of hematocrit and
WBC.
Post-Marketing
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy
(a clinical syndrome secondary to infarction of the pituitary gland) have been reported
after the administration of gonadotropin-releasing hormone agonists. In a majority of
these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy
cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.
Immediate medical attention has been required.
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Cardiovascular adverse events: Cases of serious venous and arterial thromboembolism
have been reported, including deep vein thrombosis, pulmonary embolism, myocardial
infarction, stroke, and transient ischemic attack. Although a temporal relationship was
reported in some cases, most cases were confounded by risk factors or concomitant
medication use. It is unknown if there is a causal association between the use of GnRH
analogs and these events.
OVERDOSAGE
In experimental animals, a single subcutaneous administration of up to 60 times the
recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no
adverse effects. At present, there is no clinical evidence of adverse effects following
overdosage of GnRH analogs.
Based on studies in monkeys, SYNAREL is not absorbed after oral administration.
DOSAGE AND ADMINISTRATION
For the management of endometriosis, the recommended daily dose of SYNAREL is 400
µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray
into the other nostril in the evening. Treatment should be started between days 2 and 4 of
the menstrual cycle.
In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these
patients with persistent regular menstruation after 2 months of treatment, the dose of
SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one
spray into each nostril in the morning (a total of two sprays) and again in the evening.
The recommended duration of administration is six months. Retreatment cannot be
recommended because safety data for retreatment are not available. If the symptoms of
endometriosis recur after a course of therapy, and further treatment with SYNAREL is
contemplated, it is recommended that bone density be assessed before retreatment begins
to ensure that values are within normal limits.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, because this may impair drug absorption.
At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the
daily dose is increased, increase the supply to the patient to ensure uninterrupted
treatment for the recommended duration of therapy.
HOW SUPPLIED
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate)
Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump
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that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient
instructions are also included.
Store upright at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP
Controlled Room Temperature]. Protect from light.
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LAB-0173-5.0
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SYNAREL
nafarelin acetate
Nasal Spray
Patient Instructions for Use
Introduction
Your doctor has prescribed SYNAREL Nasal Solution to treat your symptoms
of endometriosis. This pamphlet has two purposes:
1) to review information your doctor has given you about SYNAREL; and
2) to give you information about how to use SYNAREL properly.
Please read this pamphlet carefully. If you still have questions after reading it
or if you have questions at any time during your treatment with SYNAREL, be
sure to check with your doctor.
SYNAREL is used to relieve the symptoms of endometriosis. The lining of the
uterus is called the endometrium, and part of it is shed during menses. In
endometriosis, endometrial tissue is also found outside the uterus and, like
normal endometrial tissue, can bleed during a menstrual cycle. It is, in part,
this monthly activity that causes you to have symptoms during your cycle.
Most often, this out-of-place endometrial tissue is found around the uterus,
ovaries, the intestine or other organs in the pelvis. Although some women
with endometriosis have no symptoms, many have problems such as severe
menstrual cramps, pain during sexual intercourse, low back pain, and painful
bowel movements.
Endometrial tissue is affected by the body’s hormones, especially estrogen,
which is made by the ovaries. When estrogen levels are low, endometrial
tissue shrinks (perhaps even disappears), and symptoms of endometriosis
ease. SYNAREL temporarily reduces estrogen in the body and temporarily
relieves the symptoms of endometriosis.
Important Information about SYNAREL
1. You should not use SYNAREL if
• you are pregnant.
• you are breast feeding.
• you have abnormal vaginal bleeding that has not been checked
into by your doctor.
• you are allergic to any of the ingredients of SYNAREL (nafarelin
acetate, benzalkonium chloride, acetic acid, sodium hydroxide,
hydrochloric acid, sorbitol, purified water).
2. SYNAREL is a prescription medicine that should be used according to
your doctor’s directions. SYNAREL comes as a special nasal spray that
gives a measured amount of medicine. To be effective, SYNAREL must
be used every day, twice a day, for the whole treatment period.
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3. It is important to use a non-hormonal method of contraception (such
as diaphragm with contraceptive jelly, IUD, condoms) while taking
SYNAREL. You should not use birth control pills while taking SYNAREL.
4. If you miss 1 or more doses of SYNAREL, vaginal bleeding (often called
breakthrough bleeding) may occur. If you miss successive doses of
SYNAREL and have not been using contraception as described above,
release of an egg from the ovary (ovulation) may occur, with the
possibility of pregnancy. Under these circumstances you must see your
physician to make sure you are not pregnant. If you should become
pregnant while using SYNAREL, you must discuss the possible risks to
the fetus and the choices available to you with your physician.
5. Because SYNAREL works by temporarily reducing the body’s
production of estrogen, a female hormone produced by the ovary, you
may have some of the same changes that normally occur at the time
of menopause, when the body’s production of estrogen naturally
decreases. For the first two months after you start using SYNAREL,
you may experience some irregular vaginal spotting or bleeding. The
duration and intensity of this bleeding may vary; it may be similar to
your usual menstruation, or it may be lighter or heavier. The duration
may also vary from brief to prolonged. In any case, you can expect
this bleeding to stop by itself. After the first two months of treatment
with SYNAREL, you can expect a decrease in menstrual flow, and your
periods may stop altogether. However, if you miss one or more doses
of SYNAREL, you may continue to experience vaginal bleeding. If you
continue to experience normal menstrual cycles after two months use
of SYNAREL, you should see your doctor about the continued periods.
Other changes due to decreased estrogen include hot flashes, vaginal
dryness, headaches, mood changes, and decreased interest in sex.
Most of these changes are caused by low estrogen levels and may
occur during treatment with SYNAREL. Some patients may also
experience acne, muscle pain, reduced breast size, and irritation of the
tissues inside the nose. These symptoms should disappear after you
stop taking the drug.
6. When you take SYNAREL, your estrogen levels will be low. Low
estrogen levels can result in a small loss of mineral from bone, some
of which may not be reversible. During one six-month treatment
period, this small loss of mineral from bone should not be important.
There are certain conditions that may increase the possibility of the
thinning of your bones when you take a drug such as SYNAREL. They
are:
• excessive use of alcohol;
• smoking;
• family history of osteoporosis (thinning of the bones with
fractures);
• taking other medications that can cause thinning of the bones.
You should discuss the possibility of osteoporosis or thinning of the
bones with your physician before starting SYNAREL. You should also be
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aware that repeat treatments are not recommended because they may
put you at greater risk of bone thinning, particularly if you have the
above conditions.
7. During studies, menstruation usually resumed within 2 to 3 months of
stopping treatment with SYNAREL. At the end of treatment 60% of
patients treated with SYNAREL were symptom free, 32% had mild
symptoms, 7% had moderate symptoms and 1% had severe
symptoms.
Of the 60% of patients who had complete relief of symptoms at the
end of treatment, 17% had moderate symptoms at the end of the six
month post-treatment period; 33% had mild symptoms; 50% were
symptom free; no patient had severe symptoms.
8. Retreatment cannot be recommended because the safety of such
retreatment is not known.
9. It is all right to use a nasal decongestant spray while you are being
treated with SYNAREL if you follow these simple rules. Use SYNAREL
first. Wait at least 2 hours after using SYNAREL before you use the
decongestant spray.
10.You should avoid sneezing during or immediately after using SYNAREL,
if possible, because sneezing may impair drug absorption.
Proper use of SYNAREL for Treatment of Endometriosis
1. When you start to use SYNAREL, the first dose should be taken
between the second and fourth day after the beginning of your
menstrual bleeding. You should continue taking SYNAREL every day as
prescribed.
Do not miss a single dose.
2. Unless your doctor has given you special instructions, follow the steps
for using SYNAREL twice each day, about 12 hours between doses:
•
once in the morning in one nostril (for example, 7 a.m.)
•
once in the evening in the other nostril (for example, 7 p.m.)
The length of treatment is usually about 6 months, unless your doctor
has given you special instructions.
3. Because it is so important that you do not miss a single dose of
SYNAREL, here are some suggestions to help you remember:
• Keep your SYNAREL in a place where you will be reminded to
use it each morning and each evening — next to your
toothbrush is one possibility.
• Keep track of each dose on a calendar.
• Make a note on your calendar on the day you start a new bottle
of SYNAREL. You can also mark the date you started right on
the bottle. Be sure to refill your prescription before the 30 days
are up so you will have a new bottle on hand.
Reference ID: 2886729
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4. A bottle of SYNAREL should not be used for longer than 30 days (60
sprays). Each bottle contains sufficient quantity of nasal solution for
initial priming of the pump and 30 days (60 sprays) of treatment. At
the end of 30 days, a small amount of liquid will be left in the bottle.
Do not try to use up that leftover amount because you might get
too low a dose, which could interfere with the effectiveness of your
treatment. Dispose of the bottle and do not reuse.
5. If your doctor increases your daily dose of SYNAREL, then your bottle
will not last the standard 30 days. Please discuss this with your doctor
to be sure that you have an adequate supply for uninterrupted
treatment with SYNAREL to complete the recommended treatment
period.
Preparation of the SYNAREL Nasal Spray unit
For use in your nose only.
Before you use SYNAREL nasal spray for the first time, you will need
to prime it. This will ensure that you get the right dose of medicine each
time you use it.
Important Tips about using SYNAREL
• Your pump should produce a fine mist, which can only happen by a
quick and firm pumping action. It is normal to see some larger
droplets of liquid within the fine mist. However, if SYNAREL comes out
of the pump as a thin stream of liquid instead of a fine mist, SYNAREL
may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use. (See
Step 4). Failure to do this may result in a clogged tip that may cause
you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter
how hard you pump it.
• Do Not try to make the tiny hole in the spray tip larger. If the
hole is made larger the pump will deliver a wrong dose of SYNAREL.
Figure A usage illustration
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To Prime the Pump:
1. Remove and save the white safety clip and the clear
plastic dust cover from the spray bottle (See Figure
B).
usage illustrationusage illustrationusage illustration
Figure C
2. Hold the bottle in an upright position away from
you. Put two fingers on the “shoulders” of the spray
bottle and put your thumb on the bottom of the
bottle. Apply pressure evenly to the “shoulders”
and push down quickly and firmly 7 to 10 times,
until you see a fine spray. Usually you will see the
spray after about 7 pumps. (See Figure C).
3. The pump is now primed. Priming only needs to
be done 1 time, when you start using a new
bottle of SYNAREL. You will waste your medicine
if you prime the pump every time you use it and
may not have enough medicine for 30 days of
treatment.
Figure D
4. Clean the Spray Tip after Priming:
• Hold the bottle in a horizontal position. Rinse
the spray tip with warm water while wiping the
tip with your finger or soft cloth for 15 seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Replace the white safety clip and the clear
plastic dust cover on the spray bottle (See
Figure D).
• Do Not try to clean the spray tip using a
pointed object. Do Not take apart the pump.
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How to use the SYNAREL Nasal Spray unit for the treatment of
Endometriosis
Figure E
5. Gently blow your nose to clear both nostrils before
you use SYNAREL nasal spray (See Figure E). usage illustrationusage illustration
Figure F
6. Clean the Spray Tip. Remove and save the white
safety clip and the clear plastic dust cover from the
spray bottle (See Figure F).
• Hold the bottle in a horizontal position. Rinse the
spray tip with warm water while wiping the tip
with your finger or soft cloth for 15 seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Do Not try to clean the spray tip using a pointed
object.
• Do Not try to take apart the pump.
7. Bend your head forward and put the spray tip into
one nostril. The tip should not reach too far into your
nose. Aim the spray tip toward the back and outer
side of your nose (See Figure G).
usage illustrationusage illustration
Figure H
8. Close the other nostril with your finger (See Figure
H).
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usage illustration
9. Apply pressure evenly to the “shoulders” and push
down quickly and firmly. Pump the sprayer 1 time,
at the same time as you sniff in gently. If the sprayer
fails to deliver the dose clean the spray tip (See Step
6 Clean the Spray Tip).
10.Remove the spray tip from your nose and tilt your
head backwards for a few seconds. This lets the
SYNAREL spray spread over the back of your nose
(See Figure I).
Do not spray in your other nostril unless your
doctor has instructed you to do so. usage illustration
Figure J
11.Clean the Spray Tip after use (See Step 4).
It is important that you clean the spray tip before and after every
use. Failure to do this may result in a clogged tip that may cause you
to get the wrong dose of medicine.
Important Reminder: Treatment with SYNAREL must be
uninterrupted with no missed doses to be effective.
Make sure you use SYNAREL exactly as your doctor tells you. Make sure to
note the date you start each bottle so you do not run out of medicine and
miss doses.
Keep out of the reach of children and use carefully as directed.
Storage Instructions:
•
Store SYNAREL at 59°F to 86°F (15°C to 30°C).
•
Store the SYNAREL bottle upright.
•
Keep SYNAREL out of the light.
•
Do not freeze SYNAREL.
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company logo
Revised: December 2010
LAB-0278-3.3
Reference ID: 2886729
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SYNAREL
nafarelin acetate
Nasal Spray
Patient Instructions for Use
Introduction
The doctor has prescribed SYNAREL Nasal Solution to treat your child’s
abnormally early sexual development, which is called central precocious
puberty. This pamphlet has two purposes:
1) to review information your doctor has given you about SYNAREL; and
2) to give you information about how to use SYNAREL properly.
Please read this pamphlet carefully. If you still have questions after reading it
or if you have questions at any time during your child’s treatment with
SYNAREL, be sure to check with your child’s doctor.
“Central precocious puberty” is called by that name because it is sexual
development and growth (puberty) which happens at an abnormally young
age (precocious). It is caused by early awakening of a small gland in the
brain. Because the brain is part of the “central nervous system,” this early
sexual development is called “central.”
In children, SYNAREL is used to relieve the symptoms of central precocious
puberty (CPP). CPP is normal puberty that happens at an abnormally young
age. In children who are going through puberty (whether it’s normal puberty
or CPP), a small gland at the base of the brain makes some normal
substances that cause the ovaries in girls to make estrogen and
progesterone, the female hormones. In boys, it causes the testes to make
testosterone, the male hormone. Estrogen and testosterone are the
hormones that make girls and boys change into adults. These changes are
mainly of 2 kinds: sexual development and a growth spurt. Sexual
development includes things like breast and sexual hair growth and
menstruation in girls, and growth of sexual organs, sexual hair and facial
hair, and voice deepening in boys. The growth spurt during puberty occurs
when estrogen (girls) and testosterone (boys) make the long bones of the
body grow, so that the child gets taller quickly. When this growth spurt starts
at a young age as it does in CPP, children become too tall for their age, but
are usually shorter than average as adults.
SYNAREL helps relieve the symptoms of CPP by temporarily preventing the
small gland at the base of the brain from making and sending its substances
to the ovaries and testes. The ovaries and testes stop producing their
hormones as long as SYNAREL is taken regularly, and puberty is interrupted.
Reference ID: 2886729
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Important Information about SYNAREL
1. Your child should not use SYNAREL if she/he is allergic to GnRH or
GnRH agonist analogues or to any of the ingredients of SYNAREL
(nafarelin acetate, benzalkonium chloride, acetic acid, sodium
hydroxide, hydrochloric acid, sorbitol, purified water).
2. SYNAREL is a prescription medicine that should be used according to
the doctor’s directions. SYNAREL comes as a special nasal spray that
gives a measured amount of medicine.
To be effective, SYNAREL must be used every day, twice a day, until
you and your child’s doctor decide that resumption of puberty is
desired for your child. If your child doesn’t take the right amount
every day, or if she/he doesn’t take SYNAREL on the regular
prescribed schedule, pubertal development may be restarted and/or
the beneficial effects on height may be lost.
3. Menstrual flow may occur in girls during the first six weeks of
treatment, whether or not they had been menstruating before starting
treatment with SYNAREL. Menstrual flow should stop soon after the
first six weeks.
4. In children receiving SYNAREL for central precocious puberty, some
signs of puberty (for example breast enlargement in girls) may
increase during the first month of treatment. This is a normal effect of
the drug. You should continue treatment at the prescribed dose.
5. It is all right for your child to use a nasal decongestant spray while
she/he is being treated with SYNAREL if you follow these simple rules.
Use SYNAREL first. Wait at least 2 hours after using SYNAREL before
your child uses the decongestant spray.
6. Your child should avoid sneezing during or immediately after using
SYNAREL, if possible, because sneezing may impair drug absorption.
Proper Use of SYNAREL for Treatment of Central Precocious Puberty
1. When your child starts to use SYNAREL she/he should continue taking
it every day as prescribed.
Do not miss any dose.
2. Unless your child’s doctor has given you special instructions, Central
Precocious Puberty patients should follow the steps for using SYNAREL
twice each day in both nostrils, about 12 hours between doses:
• two sprays in each nostril (4 sprays total) in the morning (for
example, 7 a.m.);
• two sprays in each nostril (4 sprays total) in the evening (for
example, 7 p.m.).
The head should be tilted slightly back, and you should wait about 30
seconds between sprays into the same nostril. More detailed
instructions follow.
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3. Treatment for central precocious puberty should continue until you and
your child’s doctor decide that it is appropriate for puberty to resume.
4. Because it is so important that your child not miss a single dose of
SYNAREL, here are some suggestions to help you remember:
• Keep your child’s SYNAREL in a place where you will be
reminded for her/him to use it each morning and each evening
— next to your toothbrush is one possibility.
• Keep track of each dose on a calendar.
• Make a note on your calendar on the day you start a new bottle
of SYNAREL. You can also mark directly on the bottle the date it
was started. Be sure to refill your child’s prescription before the
7 days are up so you will have a new bottle on hand.
5. A bottle of SYNAREL for central precocious puberty patients should not
be used for longer than 7 days, unless your child’s doctor specifically
tells you it may be used for a longer time. If the doctor tells you to use
a bottle only for 7 days, then a small amount of liquid will be left in the
bottle. Do not try to use up the leftover amount because your
child might get too low a dose, which could interfere with the
effectiveness of the treatment. Dispose of the used bottle properly and
do not reuse.
6. If the doctor increases your child’s daily dose of SYNAREL, then one
bottle will not last the standard 7 days. Please discuss this with your
child’s doctor to be sure that you have an adequate supply for
uninterrupted treatment with SYNAREL.
Preparation of the SYNAREL
Nasal Spray unit
For use in your nose only.
Before you use a bottle of SYNAREL nasal spray for the first time, you
will need to prime it. This will ensure that you get the right dose of
medicine each time you use it.
Important Tips about using SYNAREL
• Your pump should produce a fine mist, which can only happen by a
quick and firm pumping action. It is normal to see some larger
droplets of liquid within the fine mist. However, if SYNAREL comes out
of the pump as a thin stream of liquid instead of a fine mist, SYNAREL
may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use. (See
Step 4). Failure to do this may result in a clogged tip that may cause
you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter
how hard you pump it.
Reference ID: 2886729
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• Do Not try to make the tiny hole in the spray tip larger. If the
hole is made larger the pump will deliver a wrong dose of SYNAREL.
Figure A usage illustration
To Prime the Pump:
1. Remove and save the white safety clip and the
clear plastic dust cover from the spray bottle (See
Figure B).
usage ill
ustration
2. Hold the bottle in an upright position away from
you. Put two fingers on the “shoulders” of the
spray bottle and put your thumb on the bottom of
the bottle. Apply pressure evenly to the
“shoulders” and push down quickly and firmly 7
to 10 times, until you see a fine spray. Usually
you will see the spray after about 7 pumps. (See
Figure C).
3. The pump is now primed. Priming only needs
to be done 1 time, when you start using a
new bottle of SYNAREL. You will waste your
medicine if you prime the pump every time you
use it and may not have enough medicine for the
recommended treatment period.
Reference ID: 2886729
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
usage ill
ustration
Figure D
4. Clean the Spray Tip after Priming:
• Hold the bottle in horizontal position. Rinse
spray the tip with warm water while wiping
the tip with your finger or soft cloth for 15
seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Replace the white safety clip and the clear
plastic dust cover on the spray bottle. (See
Figure D).
• Do Not try to clean the spray tip using a
pointed object. Do Not take apart the pump.
How to use the SYNAREL Nasal Spray unit for the treatment of
Central Precocious Puberty
5. Have your child blow their nose to clear both
nostrils before SYNAREL nasal spray is used. If
the child is young, you may need to clear the
child’s nostrils with a bulb syringe (See Figure E). usage illustration
6. Clean the Spray Tip. Remove and save the
white safety clip and the clear plastic dust cover
from the spray bottle (See Figure F).
• Hold the bottle in horizontal position. Rinse
the spray tip with warm water while wiping
the tip with your finger or soft cloth for 15
seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Do Not try to clean the spray tip using a
pointed object.
• Do Not try to take apart the pump.
Figure G
7. The child’s head should be bent back a little and
the spray tip put into one nostril. The tip should
not reach too far into the nose. Aim the spray tip
toward the back and outer side of the nose
(See Figure G).
Reference ID: 2886729
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Figure H
8. Close the other nostril with a finger (See Figure
H). usage illustration
9. Apply pressure evenly to the “shoulders” and
push down quickly and firmly. Pump the
sprayer 1 time, at the same time as the child
sniffs in gently. Wait about 30 seconds and apply
one more spray in the same nostril. Repeat this
process in the other nostril, for a total of four
sprays. If the sprayer fails to deliver the dose
clean the spray tip (See Step 6 Clean the Spray
Tip).
10.Remove the spray tip from the child’s nose after
all sprays are completed. Keep the child’s head
tilted backwards for a few seconds. This lets the
SYNAREL spray spread over the back of the nose
(See Figure I).
usage illustrationusage illustration
Figure J
11.Clean the Spray Tip after use (See Step 4).
It is important that you clean the spray tip before and after every
use. Failure to do this may result in a clogged tip that may cause you
to get the wrong dose of medicine.
Important Reminder: Treatment with SYNAREL must be
uninterrupted with no missed doses to be effective.
Reference ID: 2886729
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Make sure you use SYNAREL exactly as your doctor tells you to. Make sure
to note the date you start each bottle so you do not run out of medicine and
miss doses.
Keep out of the reach of children and use carefully as directed.
Storage Instructions:
•
Store SYNAREL at 59°F to 86°F (15°C to 30°C).
•
Store the SYNAREL bottle upright.
•
Keep SYNAREL out of the light.
•
Do not freeze SYNAREL. company logo
Revised: December 2010
LAB-0278-3.3
Reference ID: 2886729
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|
custom-source
|
2025-02-12T13:46:13.974210
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019886s026s027lbl.pdf', 'application_number': 19886, 'submission_type': 'SUPPL ', 'submission_number': 26}
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11,814
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Synarel®
(nafarelin acetate)
nasal solution
CENTRAL PRECOCIOUS PUBERTY
(FOR ENDOMETRIOSIS, SEE REVERSE SIDE)
PHYSICIAN LABELING
DESCRIPTION
SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to
the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution,
is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl
L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate.
Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing
hormone (GnRH).
Nafarelin acetate has the following chemical structure: structural formula
SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as
nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium
hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for SYNAREL, each actuation of the unit delivers
approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The
contents of one spray bottle are intended to deliver at least 60 sprays.
CLINICAL PHARMACOLOGY
Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone
(GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary
gonadotropins, LH and FSH, resulting in a temporary increase of gonadal
steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland.
Reference ID: 3803448
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Twice daily administration leads to decreased secretion of gonadal steroids by about 4
weeks; consequently, tissues and functions that depend on gonadal steroids for their
maintenance become quiescent.
In children, nafarelin acetate was rapidly absorbed into the systemic circulation after
intranasal administration. Maximum serum concentrations (measured by RIA) were
achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the
observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg
base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of
nafarelin following intranasal administration of a 400 µg dose was approximately 2.5
hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin
will be in children given a dose above 600 µg.
In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation
after intranasal administration. Maximum serum concentrations (measured by RIA) were
achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the
observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas
following a single dose of 400 µg base, the observed average peak concentration was 1.8
ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8%
(range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal
administration was approximately 3 hours. About 80% of nafarelin acetate was bound to
plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of
SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of
the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose
proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose
was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the
administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of
the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of
which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5-10). The activity
of the metabolites, the metabolism of nafarelin by nasal mucosa, and the
pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been
determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
When used regularly in girls and boys with central precocious puberty (CPP) at the
recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to
prepubertal levels, affects a corresponding arrest of secondary sexual development, and
slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal
bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter,
menstruation should cease.
Reference ID: 3803448
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In clinical studies the peak response of LH to GnRH stimulation was reduced from a
pubertal response to a prepubertal response (< 15 mlU/mL) within one month of
treatment.
Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in
most children within the first year of treatment to values of 5 to 6 cm/year or less.
Children with CPP are frequently taller than their chronological age peers; height for
chronological age approaches normal in most children during the second or third year of
treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone
age divided by change in chronological age) is usually abnormal (greater than 1) in
children with CPP; in most children, bone age velocity approaches normal (1) during the
first year of treatment. This results in a narrowing of the gap between bone age and
chronological age, usually by the second or third year of treatment. The mean predicted
adult height increases.
In clinical trials, breast development was arrested or regressed in 82% of girls, and
genital development was arrested or regressed in 100% of boys. Because pubic hair
growth is largely controlled by adrenal androgens, which are unaffected by nafarelin,
pubic hair development was arrested or regressed only in 54% of girls and boys.
Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all
children with CPP for whom one-year post-treatment follow-up is available (n=69). This
demonstration consisted of the appearance or return of menses, the return of pubertal
gonadotropin and gonadal sex steroid levels, and/or the advancement of secondary sexual
development. Semen analysis was normal in the two ejaculated specimens obtained thus
far from boys who have been taken off therapy to resume puberty. Fertility has not been
documented by pregnancies and the effect of long-term use of the drug on fertility is not
known.
INDICATIONS AND USAGE
FOR CENTRAL PRECOCIOUS PUBERTY
(For Endometriosis, See Reverse Side)
SYNAREL is indicated for treatment of central precocious puberty (CPP)
(gonadotropin-dependent precocious puberty) in children of both sexes.
The diagnosis of central precocious puberty (CPP) is suspected when premature
development of secondary sexual characteristics occurs at or before the age of 8 years in
girls and 9 years in boys, and is accompanied by significant advancement of bone age
and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal
gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH.
Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the
latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning
of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical
changes associated with increased intracranial pressure. Other causes of sexual precocity,
such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other
autonomous feminizing or masculinizing disorders must be excluded by proper clinical
Reference ID: 3803448
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hormonal and diagnostic imaging examinations.
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
SYNAREL;
2. Undiagnosed abnormal vaginal bleeding;
3. Use in pregnancy or in women who may become pregnant while receiving the drug.
SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rats, but not in mice or rabbits after administration of
SYNAREL during the period of organogenesis. There was a dose-related increase in fetal
mortality and a decrease in fetal weight in rats (see Pregnancy Section). The effects on
rat fetal mortality are expected consequences of the alterations in hormonal levels
brought about by the drug. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, she should be apprised of the potential hazard to the
fetus;
4. Use in women who are breast-feeding (see Nursing Mothers Section).
WARNINGS
The diagnosis of central precocious puberty (CPP) must be established before
treatment is initiated. Regular monitoring of CPP patients is needed to assess both
patient response as well as compliance. This is particularly important during the first 6 to
8 weeks of treatment to assure that suppression of pituitary-gonadal function is rapid.
Testing may include LH response to GnRH stimulation and circulating gonadal sex
steroid levels. Assessment of growth velocity and bone age velocity should begin within
3 to 6 months of treatment initiation.
Some patients may not show suppression of the pituitary-gonadal axis by clinical and/or
biochemical parameters. This may be due to lack of compliance with the recommended
treatment regimen and may be rectified by recommending that the dosing be done by
caregivers. If compliance problems are excluded, the possibility of gonadotropin
independent sexual precocity should be reconsidered and appropriate examinations
should be conducted. If compliance problems are excluded and if gonadotropin
independent sexual precocity is not present, the dose of SYNAREL may be increased to
1800 µg/day administered as 600 µg tid.
PRECAUTIONS
General
As with other drugs that stimulate the release of gonadotropins or that induce ovulation,
in adult women with endometriosis ovarian cysts have been reported to occur in the first
two months of therapy with SYNAREL. Many, but not all, of these events occurred in
women with polycystic ovarian disease. These cystic enlargements may resolve
spontaneously, generally by about four to six weeks of therapy, but in some cases may
require discontinuation of drug and/or surgical intervention. The relevance, if any, of
such events in children is unknown.
Information for Patients, Patients’ Parents or Guardians
An information pamphlet for patients is included with the product. Patients and their
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caregivers should be aware of the following information:
1. Reversibility of the suppressive effects of nafarelin has been demonstrated by the
appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex
steroid levels, and/or by advancement of secondary sexual development. Semen analysis
was normal in the two ejaculated specimens obtained thus far from boys who have been
taken off therapy to resume puberty. Fertility has not been documented by pregnancies
and the effect of long-term use of the drug on fertility is not known.
2. Patients and their caregivers should be adequately counseled to assure full compliance;
irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.
3. During the first month of treatment with SYNAREL, some signs of puberty, e.g.,
vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of
the drug. Such changes should resolve soon after the first month. lf such resolution does
not occur within the first two months of treatment, this may be due to lack of compliance
or the presence of gonadotropin independent sexual precocity. If both possibilities are
definitively excluded, the dose of SYNAREL may be increased to 1800 µg/day
administered as 600 µg tid.
4. Patients with intercurrent rhinitis should consult their physician for the use of a topical
nasal decongestant. If the use of a topical nasal decongestant is required during treatment
with SYNAREL, the decongestant should not be used until at least 2 hours following
dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, since this may impair drug absorption.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with
SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound
to plasma proteins at 4°C, drug interactions would not be expected to occur.
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies of
nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18
months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560
times the maximum recommended human intranasal dose, respectively). These multiples
of the human dose are based on the relative bioavailability of the drug by the two routes
of administration. As seen with other GnRH agonists, nafarelin acetate given to
laboratory rodents at high doses for prolonged periods induced proliferative responses
(hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase
in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a
dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas
in both sexes, and in benign testicular and ovarian tumors in the treated groups. There
was a dose-related increase in benign adrenal medullary tumors in treated female rats. In
mice, there was a dose-related increase in Harderian gland tumors in males and an
Reference ID: 3803448
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increase in pituitary adenomas in high-dose females. No metastases of these tumors were
observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal
stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and
mammalian systems. These studies provided no evidence of mutagenic potential.
Reproduction studies in male and female rats have shown full reversibility of fertility
suppression when drug treatment was discontinued after continuous administration for up
to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive
performance of mature animals has not been investigated.
Pregnancy, Teratogenic Effects
Pregnancy Category X. See ‘CONTRAINDICATIONS.’ Intramuscular SYNAREL was
administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day
(about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on
the relative bioavailability by the two routes of administration). An increase in major fetal
abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at
the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and
0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after
administration during the period of organogenesis. In rats and rabbits, there was a dose-
related increase in fetal mortality and a decrease in fetal weight with the highest dose.
Nursing Mothers
It is not known whether SYNAREL is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of SYNAREL on lactation and/or the
breastfed child have not been determined, SYNAREL should not be used by nursing
mothers.
ADVERSE REACTIONS
In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug
sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus.
In these 155 patients treated for an average of 41 months and as long as 80 months (6.7
years), adverse events most frequently reported (>3% of patients) consisted largely of
episodes occurring during the first 6 weeks of treatment as a result of the transient
stimulatory action of nafarelin upon the pituitary-gonadal axis:
acne (10%)
transient breast enlargement (8%)
vaginal bleeding (8%)
emotional lability (6%)
transient increase in pubic hair (5%)
body odor (4%)
seborrhea (3%)
Hot flashes, common in adult women treated for endometriosis, occurred in only 3% of
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treated children and were transient. Other adverse events thought to be drug-related, and
occurring in >3% of patients were rhinitis (5%) and white or brownish vaginal discharge
(3%). Approximately 3% of patients withdrew from clinical trials due to adverse events.
In one male patient with concomitant congenital adrenal hyperplasia, and who had
discontinued treatment 8 months previously to resume puberty, adrenal rest tumors were
found in the left testis. Relationship to SYNAREL is unlikely.
Regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or
computer assisted tomography (CT) of children during long-term nafarelin therapy as
well as during the post-treatment period has occasionally revealed changes in the shape
and size of the pituitary gland. These changes include asymmetry and enlargement of the
pituitary gland, and a pituitary microadenoma has been suspected in a few children. The
relationship of these findings to SYNAREL is not known.
Post-Marketing
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy
(a clinical syndrome secondary to infarction of the pituitary gland) have been reported
after the administration of gonadotropin-releasing hormone agonists. In a majority of
these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy
cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.
Immediate medical attention has been required.
Central/peripheral nervous adverse events: Convulsion.
OVERDOSAGE
In experimental animals, a single subcutaneous administration of up to 60 times the
recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no
adverse effects. At present, there is no clinical evidence of adverse effects following
overdosage of GnRH analogs.
Based on studies in monkeys, SYNAREL is not absorbed after oral administration.
DOSAGE AND ADMINISTRATION
For the treatment of central precocious puberty (CPP), the recommended daily dose of
SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate
suppression cannot be achieved at 1600 µg/day.
The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4
sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per
day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three
times a day, a total of 9 sprays per day. The patient’s head should be tilted back slightly,
and 30 seconds should elapse between sprays.
If the prescribed therapy has been well tolerated by the patient, treatment of CPP with
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SYNAREL should continue until resumption of puberty is desired.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, since this may impair drug absorption.
At 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays).
If the daily dose is increased, increase the supply to the patient to ensure uninterrupted
treatment for the duration of therapy.
HOW SUPPLIED
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate)
Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump
that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient
instructions are also included.
Store upright at 25 ° C (77 ° F); excursions permitted to 15–30 ° C (59–86 ° F) [see USP
Controlled Room Temperature]. Protect from light. company logo
Revised: August 2015
Reference ID: 3803448
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Synarel®
(nafarelin acetate)
nasal solution
ENDOMETRIOSIS
(FOR CENTRAL PRECOCIOUS PUBERTY,
SEE REVERSE SIDE)
PHYSICIAN LABELING
DESCRIPTION
SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to
the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution,
is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl
L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide acetate.
Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing
hormone (GnRH).
Nafarelin acetate has the following chemical structure: structural formula
SYNAREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as
nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium
hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for SYNAREL, each actuation of the unit delivers
approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The
contents of one spray bottle are intended to deliver at least 60 sprays.
CLINICAL PHARMACOLOGY
Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone
(GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary
gonadotropins, LH and FSH, resulting in a temporary increase of ovarian steroidogenesis.
Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily
Reference ID: 3803448
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administration leads to decreased secretion of gonadal steroids by about 4 weeks;
consequently, tissues and functions that depend on gonadal steroids for their maintenance
become quiescent.
Nafarelin acetate is rapidly absorbed into the systemic circulation after intranasal
administration. Maximum serum concentrations (measured by RIA) were achieved
between 10 and 40 minutes. Following a single dose of 200 µg base, the observed
average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a
single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL
(range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to
5.6%). The average serum half-life of nafarelin following intranasal administration is
approximately 3 hours. About 80% of nafarelin acetate is bound to plasma proteins at
4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy
women for 22 days did not lead to significant accumulation of the drug. Based on the
mean C min levels on Days 15 and 22, there appeared to be dose proportionality across the
two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose
was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the
administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of
the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of
which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5-10). The activity
of the metabolites, the metabolism of nafarelin by nasal mucosa, and the
pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been
determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing of SYNAREL.
In controlled clinical studies, SYNAREL at doses of 400 and 800 µg/day for 6 months
was shown to be comparable to danazol, 800 mg/day, in relieving the clinical symptoms
of endometriosis (pelvic pain, dysmenorrhea, and dyspareunia) and in reducing the size
of endometrial implants as determined by laparoscopy. The clinical significance of a
decrease in endometriotic lesions is not known at this time and, in addition, laparoscopic
staging of endometriosis does not necessarily correlate with severity of symptoms.
In a single controlled clinical trial, intranasal SYNAREL (nafarelin acetate) at a dose of
400 µg per day was shown to be clinically comparable to intramuscular leuprolide depot,
3.75 mg monthly, for the treatment of the symptoms (dysmenorrhea, dyspareunia and
pelvic pain) associated with endometriosis.
SYNAREL 400 µg daily induced amenorrhea in approximately 65%, 80%, and 90% of
the patients after 60, 90, and 120 days, respectively. In the first, second, and third post
treatment months, normal menstrual cycles resumed in 4%, 82%, and 100%, respectively,
of those patients who did not become pregnant.
Reference ID: 3803448
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At the end of treatment, 60% of patients who received SYNAREL, 400 µg/day, were
symptom free, 32% had mild symptoms, 7% had moderate symptoms, and 1% had severe
symptoms. Of the 60% of patients who had complete relief of symptoms at the end of
treatment, 17% had moderate symptoms 6 months after treatment was discontinued, 33%
had mild symptoms, 50% remained symptom free, and no patient had severe symptoms.
During the first two months use of SYNAREL, some women experience vaginal bleeding
of variable duration and intensity. In all likelihood, this bleeding represents estrogen
withdrawal bleeding and is expected to stop spontaneously. If vaginal bleeding continues,
the possibility of lack of compliance with the dosing regimen should be considered. If the
patient is complying carefully with the regimen, an increase in dose to 400 µg twice a day
should be considered.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use
of SYNAREL.
INDICATIONS AND USAGE FOR ENDOMETRIOSIS
(For Central Precocious Puberty, See Reverse Side)
SYNAREL is indicated for management of endometriosis, including pain relief and
reduction of endometriotic lesions. Experience with SYNAREL for the management of
endometriosis has been limited to women 18 years of age and older treated for 6 months.
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
SYNAREL;
2. Undiagnosed abnormal vaginal bleeding;
3. Use in pregnancy or in women who may become pregnant while receiving the drug.
SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rats, but not in mice or rabbits after administration of
SYNAREL during the period of organogenesis. There was a dose-related increase in fetal
mortality and a decrease in fetal weight in rats (see Pregnancy Section). The effects on
rat fetal mortality are expected consequences of the alterations in hormonal levels
brought about by the drug. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, she should be apprised of the potential hazard to the
fetus;
4. Use in women who are breast-feeding (see Nursing Mothers Section).
WARNINGS
Safe use of nafarelin acetate in pregnancy has not been established clinically. Before
starting treatment with SYNAREL, pregnancy must be excluded.
When used regularly at the recommended dose, SYNAREL usually inhibits ovulation and
stops menstruation. Contraception is not insured, however, by taking SYNAREL,
particularly if patients miss successive doses. Therefore, patients should use nonhormonal
methods of contraception. Patients should be advised to see their physician if they believe
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they may be pregnant. If a patient becomes pregnant during treatment, the drug must be
discontinued and the patient must be apprised of the potential risk to the fetus.
PRECAUTIONS
General
As with other drugs that stimulate the release of gonadotropins or that induce ovulation,
ovarian cysts have been reported to occur in the first two months of therapy with
SYNAREL. Many, but not all, of these events occurred in patients with polycystic
ovarian disease. These cystic enlargements may resolve spontaneously, generally by
about four to six weeks of therapy, but in some cases may require discontinuation of drug
and/or surgical intervention.
Information for Patients
An information pamphlet for patients is included with the product. Patients should be
aware of the following information:
1. Since menstruation should stop with effective doses of SYNAREL, the patient should
notify her physician if regular menstruation persists. The cause of vaginal spotting,
bleeding or menstruation could be noncompliance with the treatment regimen, or it could
be that a higher dose of the drug is required to achieve amenorrhea. The patient should be
questioned regarding her compliance. If she is careful and compliant, and menstruation
persists to the second month, consideration should be given to doubling the dose of
SYNAREL. If the patient has missed several doses, she should be counseled on the
importance of taking SYNAREL regularly as prescribed.
2. Patients should not use SYNAREL if they are pregnant, breastfeeding, have
undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in
SYNAREL.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a
nonhormonal method of contraception should be used during treatment. Patients should
be advised that if they miss successive doses of SYNAREL, breakthrough bleeding or
ovulation may occur with the potential for conception. If a patient becomes pregnant
during treatment, she should discontinue treatment and consult her physician.
4. Those adverse events occurring most frequently in clinical studies with SYNAREL are
associated with hypoestrogenism; the most frequently reported are hot flashes, headaches,
emotional lability, decreased libido, vaginal dryness, acne, myalgia, and reduction in
breast size. Estrogen levels returned to normal after treatment was discontinued. Nasal
irritation occurred in about 10% of all patients who used intranasal nafarelin.
5. The induced hypoestrogenic state results in a small loss in bone density over the course
of treatment, some of which may not be reversible. During one six-month treatment
period, this bone loss should not be important. In patients with major risk factors for
decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family
history of osteoporosis, or chronic use of drugs that can reduce bone mass such as
anticonvulsants or corticosteroids, therapy with SYNAREL may pose an additional risk.
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In these patients the risks and benefits must be weighed carefully before therapy with
SYNAREL is instituted. Repeated courses of treatment with gonadotropin-releasing
hormone analogs are not advisable in patients with major risk factors for loss of bone
mineral content.
6. Patients with intercurrent rhinitis should consult their physician for the use of a topical
nasal decongestant. If the use of a topical nasal decongestant is required during treatment
with SYNAREL, the decongestant should not be used until at least 2 hours following
dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, since this may impair drug absorption.
7. Retreatment cannot be recommended since safety data beyond 6 months are not
available.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with
SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound
to plasma proteins at 4°C, drug interactions would not be expected to occur.
Drug/Laboratory Test Interactions
Administration of SYNAREL in therapeutic doses results in suppression of the pituitary-
gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is
discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions
conducted during treatment and up to 4 to 8 weeks after discontinuation of therapy with
SYNAREL may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to
100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular
doses (up to 110 times and 560 times the maximum recommended human intranasal dose,
respectively). These multiples of the human dose are based on the relative bioavailability
of the drug by the two routes of administration. As seen with other GnRH agonists,
nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced
proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months,
there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-
dose female rats and a dose-related increase in male rats. There was an increase in
pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors
in the treated groups. There was a dose-related increase in benign adrenal medullary
tumors in treated female rats. In mice, there was a dose-related increase in Harderian
gland tumors in males and an increase in pituitary adenomas in high-dose females. No
metastases of these tumors were observed. It is known that tumorigenicity in rodents is
particularly sensitive to hormonal stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and
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mammalian systems. These studies provided no evidence of mutagenic potential.
Reproduction studies in male and female rats have shown full reversibility of fertility
suppression when drug treatment was discontinued after continuous administration for up
to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive
performance of mature animals has not been investigated.
Pregnancy, Teratogenic Effects
Pregnancy Category X. See ‘CONTRAINDICATIONS.’ Intramuscular SYNAREL was
administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day
(about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on
the relative bioavailability by the two routes of administration). An increase in major fetal
abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at
the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and
0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after
administration during the period of organogenesis. In rats and rabbits, there was a dose-
related increase in fetal mortality and a decrease in fetal weight with the highest dose.
Nursing Mothers
It is not known whether SYNAREL is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of SYNAREL on lactation and/or the
breastfed child have not been determined, SYNAREL should not be used by nursing
mothers.
Pediatric Use
Safety and effectiveness of SYNAREL for endometriosis in patients younger than 18
years have not been established.
ADVERSE REACTIONS
Clinical Studies
In formal clinical trials of 1509 healthy adult patients, symptoms suggestive of drug
sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus occurred in
3 patients (approximately 0.2%).
As would be expected with a drug which lowers serum estradiol levels, the most
frequently reported adverse reactions were those related to hypoestrogenism.
In controlled studies comparing SYNAREL (400 µg/day) and danazol (600 or 800
mg/day), adverse reactions most frequently reported and thought to be drug-related are
shown in the figure below:
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graph
In addition, less than 1% of patients experienced paresthesia, palpitations, chloasma,
maculopapular rash, eye pain, asthenia, lactation, breast engorgement, and arthralgia.
Changes in Bone Density
After six months of treatment with SYNAREL, vertebral trabecular bone density and
total vertebral bone mass, measured by quantitative computed tomography (QCT),
decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment
levels. There was partial recovery of bone density in the post-treatment period; the
average trabecular bone density and total bone mass were 4.9% and 3.3% less than the
pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon
absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment.
After six months treatment with SYNAREL, bone mass as measured by dual x-ray bone
densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by
DEXA six months after completion of treatment, was 1.4% below pretreatment. There
was little, if any, decrease in the mineral content in compact bone of the distal radius and
second metacarpal. Use of SYNAREL for longer than the recommended six months or in
the presence of other known risk factors for decreased bone mineral content may cause
additional bone loss.
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Changes in Laboratory Values During Treatment
Plasma enzymes. During clinical trials with SYNAREL, regular laboratory monitoring
revealed that SGOT and SGPT levels were more than twice the upper limit of normal in
only one patient each. There was no other clinical or laboratory evidence of abnormal
liver function and levels returned to normal in both patients after treatment was stopped.
Lipids. At enrollment, 9% of the patients in the group taking SYNAREL 400 µg/day and
2% of the patients in the danazol group had total cholesterol values above 250 mg/dL.
These patients also had cholesterol values above 250 mg/dL at the end of treatment.
Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in
the group treated with SYNAREL and 18% in the danazol group, had post-treatment
values above 250 mg/dL.
The mean (± SEM) pretreatment values for total cholesterol from all patients were 191.8
(4.3) mg/dL in the group treated with SYNAREL and 193.1 (4.6) mg/dL in the danazol
group. At the end of treatment, the mean values for total cholesterol from all patients
were 204.5 (4.8) mg/dL in the group treated with SYNAREL and 207.7 (5.1) mg/dL in
the danazol group. These increases from the pretreatment values were statistically
significant (p<0.05) in both groups.
Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients
who received SYNAREL and in 7% of the patients who received danazol.
At the end of treatment, no patients receiving SYNAREL had abnormally low HDL
cholesterol fractions (less than 30 mg/dL) compared with 43% of patients receiving
danazol. None of the patients receiving SYNAREL had abnormally high LDL cholesterol
fractions (greater than 190 mg/dL) compared with 15% of those receiving danazol. There
was no increase in the LDL/HDL ratio in patients receiving SYNAREL, but there was
approximately a 2-fold increase in the LDL/HDL ratio in patients receiving danazol.
Other changes. In comparative studies, the following changes were seen in
approximately 10% to 15% of patients. Treatment with SYNAREL was associated with
elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium
and WBC counts. Danazol therapy was associated with an increase of hematocrit and
WBC.
Post-Marketing
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy
(a clinical syndrome secondary to infarction of the pituitary gland) have been reported
after the administration of gonadotropin-releasing hormone agonists. In a majority of
these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy
cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.
Immediate medical attention has been required.
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Cardiovascular adverse events: Cases of serious venous and arterial thromboembolism
have been reported, including deep vein thrombosis, pulmonary embolism, myocardial
infarction, stroke, and transient ischemic attack. Although a temporal relationship was
reported in some cases, most cases were confounded by risk factors or concomitant
medication use. It is unknown if there is a causal association between the use of GnRH
analogs and these events.
Central/peripheral nervous adverse events: Convulsion.
Hepatic adverse events: Rarely reported serious liver injury.
Reproductive system adverse events: Cases of ovarian hyperstimulation syndrome have
been reported with Synarel monotherapy when used for Assisted Reproductive
Technology which is not an approved indication.
OVERDOSAGE
In experimental animals, a single subcutaneous administration of up to 60 times the
recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no
adverse effects. At present, there is no clinical evidence of adverse effects following
overdosage of GnRH analogs.
Based on studies in monkeys, SYNAREL is not absorbed after oral administration.
DOSAGE AND ADMINISTRATION
For the management of endometriosis, the recommended daily dose of SYNAREL is 400
µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray
into the other nostril in the evening. Treatment should be started between days 2 and 4 of
the menstrual cycle.
In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these
patients with persistent regular menstruation after 2 months of treatment, the dose of
SYNAREL may be increased to 800 µg daily. The 800 µg dose is administered as one
spray into each nostril in the morning (a total of two sprays) and again in the evening.
The recommended duration of administration is six months. Retreatment cannot be
recommended since safety data for retreatment are not available. If the symptoms of
endometriosis recur after a course of therapy, and further treatment with SYNAREL is
contemplated, it is recommended that bone density be assessed before retreatment begins
to ensure that values are within normal limits.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the
systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for
rhinitis is necessary during treatment with SYNAREL, the decongestant should not be
used until at least 2 hours following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if
possible, since this may impair drug absorption.
At 400 µg/day, a bottle of SYNAREL provides a 30-day (about 60 sprays) supply. If the
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daily dose is increased, increase the supply to the patient to ensure uninterrupted
treatment for the recommended duration of therapy.
HOW SUPPLIED
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL SYNAREL (nafarelin acetate)
Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump
that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient
instructions are also included.
Store upright at 25 ° C (77 ° F); excursions permitted to 15–30 ° C (59–86 ° F) [see USP
Controlled Room Temperature]. Protect from light.
Rx only company logo
Revised: August 2015
LAB-0173-7.1
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SYNAREL
nafarelin acetate
Nasal Spray
Patient Instructions for Use
Introduction
Your doctor has prescribed SYNAREL Nasal Solution to treat your symptoms
of endometriosis. This pamphlet has two purposes:
1.) to review information your doctor has given you about SYNAREL; and
2.) to give you information about how to use SYNAREL properly.
Please read this pamphlet carefully. If you still have questions after reading it
or if you have questions at any time during your treatment with SYNAREL, be
sure to check with your doctor.
SYNAREL is used to relieve the symptoms of endometriosis. The lining of the
uterus is called the endometrium, and part of it is shed during menses. In
endometriosis, endometrial tissue is also found outside the uterus and, like
normal endometrial tissue, can bleed during a menstrual cycle. It is, in part,
this monthly activity that causes you to have symptoms during your cycle.
Most often, this out-of-place endometrial tissue is found around the uterus,
ovaries, the intestine or other organs in the pelvis. Although some women
with endometriosis have no symptoms, many have problems such as severe
menstrual cramps, pain during sexual intercourse, low back pain, and painful
bowel movements.
Endometrial tissue is affected by the body’s hormones, especially estrogen,
which is made by the ovaries. When estrogen levels are low, endometrial
tissue shrinks (perhaps even disappears), and symptoms of endometriosis
ease. SYNAREL temporarily reduces estrogen in the body and temporarily
relieves the symptoms of endometriosis.
Important Information about SYNAREL
1. You should not use SYNAREL if
• you are pregnant.
• you are breast feeding.
• you have abnormal vaginal bleeding that has not been checked
into by your doctor.
• you are allergic to any of the ingredients of SYNAREL (nafarelin
acetate, benzalkonium chloride, acetic acid, sodium hydroxide,
hydrochloric acid, sorbitol, purified water).
2. SYNAREL is a prescription medicine that should be used according to
your doctor’s directions. SYNAREL comes as a special nasal spray that
gives a measured amount of medicine. To be effective, SYNAREL must
be used every day, twice a day, for the whole treatment period.
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3. It is important to use a non-hormonal method of contraception (such
as diaphragm with contraceptive jelly, IUD, condoms) while taking
SYNAREL. You should not use birth control pills while taking SYNAREL.
4. If you miss 1 or more doses of SYNAREL, vaginal bleeding (often called
breakthrough bleeding) may occur. If you miss successive doses of
SYNAREL and have not been using contraception as described above,
release of an egg from the ovary (ovulation) may occur, with the
possibility of pregnancy. Under these circumstances you must see your
physician to make sure you are not pregnant. If you should become
pregnant while using SYNAREL, you must discuss the possible risks to
the fetus and the choices available to you with your physician.
5. Because SYNAREL works by temporarily reducing the body’s
production of estrogen, a female hormone produced by the ovary, you
may have some of the same changes that normally occur at the time
of menopause, when the body’s production of estrogen naturally
decreases. For the first two months after you start using SYNAREL,
you may experience some irregular vaginal spotting or bleeding. The
duration and intensity of this bleeding may vary; it may be similar to
your usual menstruation, or it may be lighter or heavier. The duration
may also vary from brief to prolonged. In any case, you can expect
this bleeding to stop by itself. After the first two months of treatment
with SYNAREL, you can expect a decrease in menstrual flow, and your
periods may stop altogether. However, if you miss one or more doses
of SYNAREL, you may continue to experience vaginal bleeding. If you
continue to experience normal menstrual cycles after two months use
of SYNAREL, you should see your doctor about the continued periods.
Other changes due to decreased estrogen include hot flashes, vaginal
dryness, headaches, mood changes, and decreased interest in sex.
Most of these changes are caused by low estrogen levels and may
occur during treatment with SYNAREL. Some patients may also
experience acne, muscle pain, reduced breast size, and irritation of the
tissues inside the nose. These symptoms should disappear after you
stop taking the drug.
6. When you take SYNAREL, your estrogen levels will be low. Low
estrogen levels can result in a small loss of mineral from bone, some
of which may not be reversible. During one six-month treatment
period, this small loss of mineral from bone should not be important.
There are certain conditions that may increase the possibility of the
thinning of your bones when you take a drug such as SYNAREL. They
are:
• excessive use of alcohol;
• smoking;
• family history of osteoporosis (thinning of the bones with
fractures);
•
taking other medications that can cause thinning of the bones.
You should discuss the possibility of osteoporosis or thinning of the
bones with your physician before starting SYNAREL. You should also be
aware that repeat treatments are not recommended since they may
put you at greater risk of bone thinning, particularly if you have the
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above conditions.
7. During studies, menstruation usually resumed within 2 to 3 months of
stopping treatment with SYNAREL. At the end of treatment 60% of
patients treated with SYNAREL were symptom free, 32% had mild
symptoms, 7% had moderate symptoms and 1% had severe
symptoms.
Of the 60% of patients who had complete relief of symptoms at the
end of treatment, 17% had moderate symptoms at the end of the six
month post-treatment period; 33% had mild symptoms; 50% were
symptom free; no patient had severe symptoms.
8. Retreatment cannot be recommended since the safety of such
retreatment is not known.
9. It is all right to use a nasal decongestant spray while you are being
treated with SYNAREL if you follow these simple rules. Use SYNAREL
first. Wait at least 2 hours after using SYNAREL before you use the
decongestant spray.
10.You should avoid sneezing during or immediately after using SYNAREL,
if possible, since sneezing may impair drug absorption.
Proper use of SYNAREL for Treatment of Endometriosis
1. When you start to use SYNAREL, the first dose should be taken
between the second and fourth day after the beginning of your
menstrual bleeding. You should continue taking SYNAREL every day as
prescribed.
Do not miss a single dose.
2. Unless your doctor has given you special instructions, follow the steps
for using SYNAREL twice each day, about 12 hours between doses:
•
once in the morning in one nostril (for example, 7 a.m.)
•
once in the evening in the other nostril (for example, 7 p.m.)
The length of treatment is usually about 6 months, unless your doctor
has given you special instructions.
3. Because it is so important that you do not miss a single dose of
SYNAREL, here are some suggestions to help you remember:
• Keep your SYNAREL in a place where you will be reminded to
use it each morning and each evening — next to your
toothbrush is one possibility.
• Keep track of each dose on a calendar.
• Make a note on your calendar on the day you start a new bottle
of SYNAREL. You can also mark the date you started right on
the bottle. Be sure to refill your prescription before the 30 days
are up so you will have a new bottle on hand.
4. A bottle of SYNAREL should not be used for longer than 30 days (60
sprays). Each bottle contains sufficient quantity of nasal solution for
initial priming of the pump and 30 days (60 sprays) of treatment. At
the end of 30 days, a small amount of liquid will be left in the bottle.
Do not try to use up that leftover amount because you might get
too low a dose, which could interfere with the effectiveness of your
treatment. Dispose of the bottle and do not reuse.
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5. If your doctor increases your daily dose of SYNAREL, then your bottle
will not last the standard 30 days. Please discuss this with your doctor
to be sure that you have an adequate supply for uninterrupted
treatment with SYNAREL to complete the recommended treatment
period.
Preparation of the SYNAREL Nasal Spray unit
For use in your nose only.
Before you use SYNAREL nasal spray for the first time, you will need
to prime it. This will ensure that you get the right dose of medicine each
time you use it.
Important Tips about using SYNAREL
• Your pump should produce a fine mist, which can only happen by a
quick and firm pumping action. It is normal to see some larger
droplets of liquid within the fine mist. However, if SYNAREL comes out
of the pump as a thin stream of liquid instead of a fine mist, SYNAREL
may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use. (See
Step 4). Failure to do this may result in a clogged tip that may cause
you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter
how hard you pump it.
• Do Not try to make the tiny hole in the spray tip larger. If the
hole is made larger the pump will deliver a wrong dose of SYNAREL.
usage illustration
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To Prime the Pump:
1. Remove and save the white safety clip and the clear
plastic dust cover from the spray bottle (See Figure
B).
usage illustration
Figure C usage illustration
Figure D usage illustration
2. Hold the bottle in an upright position away from
you. Put two fingers on the “shoulders” of the spray
bottle and put your thumb on the bottom of the
bottle. Apply pressure evenly to the “shoulders”
and push down quickly and firmly 7 to 10 times,
until you see a fine spray. Usually you will see the
spray after about 7 pumps. (See Figure C).
3. The pump is now primed. Priming only needs to
be done 1 time, when you start using a new
bottle of SYNAREL. You will waste your medicine
if you prime the pump every time you use it and
may not have enough medicine for 30 days of
treatment.
4. Clean the Spray Tip after Priming:
• Hold the bottle in a horizontal position. Rinse the
spray tip with warm water while wiping the tip
with your finger or soft cloth for 15 seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Replace the white safety clip and the clear plastic
dust cover on the spray bottle (See Figure D).
• Do Not try to clean the spray tip using a pointed
object. Do Not take apart the pump.
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How to use the SYNAREL Nasal Spray unit for the treatment of usage illustration
Endometriosis
Figure E
5. Gently blow your nose to clear both nostrils before
you use SYNAREL nasal spray (See Figure E).
Figure F usage illustration
Figure G usage illustration
Figure H usage illustration
6. Clean the Spray Tip. Remove and save the white
safety clip and the clear plastic dust cover from the
spray bottle (See Figure F).
• Hold the bottle in a horizontal position. Rinse the
spray tip with warm water while wiping the tip
with your finger or soft cloth for 15 seconds.
• Wipe the spray tip with a soft cloth or tissue to
dry.
• Do Not try to clean the spray tip using a pointed
object.
• Do Not try to take apart the pump.
7. Bend your head forward and put the spray tip into
one nostril. The tip should not reach too far into your
nose. Aim the spray tip toward the back and outer
side of your nose (See Figure G).
8. Close the other nostril with your finger (See Figure
H).
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usage illustration
9. Apply pressure evenly to the “shoulders” and push
down quickly and firmly. Pump the sprayer 1 time,
at the same time as you sniff in gently. If the sprayer
fails to deliver the dose clean the spray tip (See Step
6 Clean the Spray Tip).
10.Remove the spray tip from your nose and tilt your
head backwards for a few seconds. This lets the
SYNAREL spray spread over the back of your nose
(See Figure I).
Do not spray in your other nostril unless your
doctor has instructed you to do so.
Figure J
11.
Clean the Spray Tip after use (See Step 4). usage illustration
It is important that you clean the spray tip before and after every
use. Failure to do this may result in a clogged tip that may cause you
to get the wrong dose of medicine.
Important Reminder: Treatment with SYNAREL must be
uninterrupted with no missed doses to be effective.
Make sure you use SYNAREL exactly as your doctor tells you. Make sure to
note the date you start each bottle so you do not run out of medicine and
miss doses.
Keep out of the reach of children and use carefully as directed.
Storage Instructions:
•
Store SYNAREL at 59°F to 86°F (15°C to 30°C).
•
Store the SYNAREL bottle upright.
•
Keep SYNAREL out of the light.
•
Do not freeze SYNAREL.
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This product’s label may have been updated. For current full prescribing
information, please visit www.pfizer.com. company logo
Revised: August 2015
LAB-0278-5.0
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SYNAREL
nafarelin acetate
Nasal Spray
Patient Instructions for Use
Introduction
The doctor has prescribed SYNAREL Nasal Solution to treat your child’s
abnormally early sexual development, which is called central precocious
puberty. This pamphlet has two purposes:
1) to review information your doctor has given you about SYNAREL; and
2) to give you information about how to use SYNAREL properly.
Please read this pamphlet carefully. If you still have questions after reading it
or if you have questions at any time during your child’s treatment with
SYNAREL, be sure to check with your child’s doctor.
“Central precocious puberty” is called by that name because it is sexual
development and growth (puberty) which happens at an abnormally young
age (precocious). It is caused by early awakening of a small gland in the
brain. Since the brain is part of the “central nervous system,” this early
sexual development is called “central.”
In children, SYNAREL is used to relieve the symptoms of central precocious
puberty (CPP). CPP is normal puberty that happens at an abnormally young
age. In children who are going through puberty (whether it’s normal puberty
or CPP), a small gland at the base of the brain makes some normal
substances that cause the ovaries in girls to make estrogen and
progesterone, the female hormones. In boys, it causes the testes to make
testosterone, the male hormone. Estrogen and testosterone are the
hormones that make girls and boys change into adults. These changes are
mainly of 2 kinds: sexual development and a growth spurt. Sexual
development includes things like breast and sexual hair growth and
menstruation in girls, and growth of sexual organs, sexual hair and facial
hair, and voice deepening in boys. The growth spurt during puberty occurs
when estrogen (girls) and testosterone (boys) make the long bones of the
body grow, so that the child gets taller quickly. When this growth spurt starts
at a young age as it does in CPP, children become too tall for their age, but
are usually shorter than average as adults.
SYNAREL helps relieve the symptoms of CPP by temporarily preventing the
small gland at the base of the brain from making and sending its substances
to the ovaries and testes. The ovaries and testes stop producing their
hormones as long as SYNAREL is taken regularly, and puberty is interrupted.
Reference ID: 3803448
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Important Information about SYNAREL
1. Your child should not use SYNAREL if she/he is allergic to GnRH or
GnRH agonist analogues or to any of the ingredients of SYNAREL
(nafarelin acetate, benzalkonium chloride, acetic acid, sodium
hydroxide, hydrochloric acid, sorbitol, purified water).
2. SYNAREL is a prescription medicine that should be used according to
the doctor’s directions. SYNAREL comes as a special nasal spray that
gives a measured amount of medicine.
To be effective, SYNAREL must be used every day, twice a day, until
you and your child’s doctor decide that resumption of puberty is
desired for your child. If your child doesn’t take the right amount
every day, or if she/he doesn’t take SYNAREL on the regular
prescribed schedule, pubertal development may be restarted and/or
the beneficial effects on height may be lost.
3. Menstrual flow may occur in girls during the first six weeks of
treatment, whether or not they had been menstruating before starting
treatment with SYNAREL. Menstrual flow should stop soon after the
first six weeks.
4. In children receiving SYNAREL for central precocious puberty, some
signs of puberty (for example breast enlargement in girls) may
increase during the first month of treatment. This is a normal effect of
the drug. You should continue treatment at the prescribed dose.
5. It is all right for your child to use a nasal decongestant spray while
she/he is being treated with SYNAREL if you follow these simple rules.
Use SYNAREL first. Wait at least 2 hours after using SYNAREL before
your child uses the decongestant spray.
6. Your child should avoid sneezing during or immediately after using
SYNAREL, if possible, since sneezing may impair drug absorption.
Proper Use of SYNAREL for Treatment of Central Precocious Puberty
1. When your child starts to use SYNAREL she/he should continue taking
it every day as prescribed.
Do not miss any dose.
2. Unless your child’s doctor has given you special instructions, Central
Precocious Puberty patients should follow the steps for using SYNAREL
twice each day in both nostrils, about 12 hours between doses:
• two sprays in each nostril (4 sprays total) in the morning (for
example, 7 a.m.);
• two sprays in each nostril (4 sprays total) in the evening (for
example, 7 p.m.).
The head should be tilted slightly back, and you should wait about 30
seconds between sprays into the same nostril. More detailed
instructions follow.
3. Treatment for central precocious puberty should continue until you and
your child’s doctor decide that it is appropriate for puberty to resume.
4. Because it is so important that your child not miss a single dose of
SYNAREL, here are some suggestions to help you remember:
Reference ID: 3803448
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• Keep your child’s SYNAREL in a place where you will be
reminded for her/him to use it each morning and each evening
— next to your toothbrush is one possibility.
• Keep track of each dose on a calendar.
• Make a note on your calendar on the day you start a new bottle
of SYNAREL. You can also mark directly on the bottle the date it
was started. Be sure to refill your child’s prescription before the
7 days are up so you will have a new bottle on hand.
5. A bottle of SYNAREL for central precocious puberty patients should not
be used for longer than 7 days, unless your child’s doctor specifically
tells you it may be used for a longer time. If the doctor tells you to use
a bottle only for 7 days, then a small amount of liquid will be left in the
bottle. Do not try to use up the leftover amount because your
child might get too low a dose, which could interfere with the
effectiveness of the treatment. Dispose of the used bottle properly and
do not reuse.
6. If the doctor increases your child’s daily dose of SYNAREL, then one
bottle will not last the standard 7 days. Please discuss this with your
child’s doctor to be sure that you have an adequate supply for
uninterrupted treatment with SYNAREL.
Preparation of the SYNAREL
Nasal Spray unit
For use in your nose only.
Before you use a bottle of SYNAREL nasal spray for the first time, you
will need to prime it. This will ensure that you get the right dose of
medicine each time you use it.
Important Tips about using SYNAREL
• Your pump should produce a fine mist, which can only happen by a
quick and firm pumping action. It is normal to see some larger
droplets of liquid within the fine mist. However, if SYNAREL comes out
of the pump as a thin stream of liquid instead of a fine mist, SYNAREL
may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use. (See
Step 4). Failure to do this may result in a clogged tip that may cause
you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter
how hard you pump it.
• Do Not try to make the tiny hole in the spray tip larger. If the
hole is made larger the pump will deliver a wrong dose of SYNAREL.
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure A usage illustration
To Prime the Pump:
1. Remove and save the white safety clip and the
clear plastic dust cover from the spray bottle (See
Figure B).
usage ill
ustration
2. Hold the bottle in an upright position away from
you. Put two fingers on the “shoulders” of the
spray bottle and put your thumb on the bottom of
the bottle. Apply pressure evenly to the
“shoulders” and push down quickly and firmly 7
to 10 times, until you see a fine spray. Usually
you will see the spray after about 7 pumps. (See
Figure C).
3. The pump is now primed. Priming only needs
to be done 1 time, when you start using a
new bottle of SYNAREL. You will waste your
medicine if you prime the pump every time you
use it and may not have enough medicine for the
recommended treatment period.
4. Clean the Spray Tip after Priming:
• Hold the bottle in horizontal position. Rinse
spray the tip with warm water while wiping
Reference ID: 3803448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
the tip with your finger or soft cloth for 15
seconds.
Figure D
• Wipe the spray tip with a soft cloth or
tissue to dry.
• Replace the white safety clip and the clear
plastic dust cover on the spray bottle. (See
Figure D).
• Do Not try to clean the spray tip using a
pointed object. Do Not take apart the
pump. usage illustration
How to use the SYNAREL Nasal Spray unit for the treatment of
Central Precocious Puberty
5. Have your child blow their nose to clear both
nostrils before SYNAREL nasal spray is used. If the
child is young, you may need to clear the child’s
nostrils with a bulb syringe (See Figure E).
usage illustrationusage illustration
Figure F
6. Clean the Spray Tip. Remove and save the white
safety clip and the clear plastic dust cover from the
spray bottle (See Figure F).
Hold the bottle in horizontal position. Rinse the
spray tip with warm water while wiping the tip
with your finger or soft cloth for 15 seconds.
Wipe the spray tip with a soft cloth or tissue to
dry.
Do Not try to clean the spray tip using a pointed
object.
Do Not try to take apart the pump.
Figure G
7. The child’s head should be bent back a little and
the spray tip put into one nostril. The tip should
not reach too far into the nose. Aim the spray tip
toward the back and outer side of the nose
(See Figure G). usage illustration
Reference ID: 3803448
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Figure H
8. Close the other nostril with a finger (See Figure
H). usage illustration
9. Apply pressure evenly to the “shoulders” and
push down quickly and firmly. Pump the
sprayer 1 time, at the same time as the child
sniffs in gently. Wait about 30 seconds and apply
one more spray in the same nostril. Repeat this
process in the other nostril, for a total of four
sprays. If the sprayer fails to deliver the dose
clean the spray tip (See Step 6 Clean the Spray
Tip).
10.Remove the spray tip from the child’s nose after
all sprays are completed. Keep the child’s head
tilted backwards for a few seconds. This lets the
SYNAREL spray spread over the back of the nose
(See Figure I).
usage illustration
Figure J
11. Clean the Spray Tip after use (See Step 4). usage illustration
It is important that you clean the spray tip before and after every
use. Failure to do this may result in a clogged tip that may cause you
to get the wrong dose of medicine.
Important Reminder: Treatment with SYNAREL must be
uninterrupted with no missed doses to be effective.
Make sure you use SYNAREL exactly as your doctor tells you to. Make sure
to note the date you start each bottle so you do not run out of medicine and
Reference ID: 3803448
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
miss doses.
Keep out of the reach of children and use carefully as directed.
•
Storage Instructions:
•
Store SYNAREL at 59°F to 86°F (15°C to 30°C).
•
Store the SYNAREL bottle upright.
•
Keep SYNAREL out of the light.
•
Do not freeze SYNAREL.
This product’s label may have been updated. For current full prescribing
information, please visit www.pfizer.com. company logo
Revised: August 2015
LAB-0278-5.0
Reference ID: 3803448
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:14.130374
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019886s032lbl.pdf', 'application_number': 19886, 'submission_type': 'SUPPL ', 'submission_number': 32}
|
11,816
|
ZESTORETIC®
(Lisinopril and Hydrochlorothiazide) Tablets
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue ZESTORETIC as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus. See Warnings: Fetal Toxicity.
DESCRIPTION
ZESTORETIC® (Lisinopril and Hydrochlorothiazide)
combines
an
angiotensin
converting
enzyme
inhibitor,
lisinopril,
and
a
diuretic,
hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme
inhibitor. It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline
dihydrate. Its empirical formula is C21H31N3O5 . 2H2O and its structural formula is: structural formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is
soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1
dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:
H
st
r
uc
t
ur
al
fo
r
mu
l
a
Reference ID: 3219425
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Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight
of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
ZESTORETIC is available for oral use in three tablet combinations of lisinopril with
hydrochlorothiazide:
ZESTORETIC 10-12.5 containing 10 mg lisinopril and 12.5 mg
hydrochlorothiazide; ZESTORETIC 20-12.5 containing 20 mg lisinopril and 12.5 mg
hydrochlorothiazide; and, ZESTORETIC 20-25 containing 20 mg lisinopril and 25 mg
hydrochlorothiazide.
Inactive Ingredients:
10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch,
yellow ferric oxide.
20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, starch.
20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch,
yellow ferric oxide.
CLINICAL PHARMACOLOGY
Lisinopril and Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases
aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the
renin-angiotensin aldosterone axis and tends to reverse the potassium loss associated with the
diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril
and hydrochlorothiazide was approximately additive. The ZESTORETIC 10-12.5 combination
worked equally well in black and white patients. The ZESTORETIC 20-12.5 and ZESTORETIC
20-25 combinations appeared somewhat less effective in black patients, but relatively few black
patients were studied. In most patients, the antihypertensive effect of ZESTORETIC was
sustained for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of ZESTORETIC 20
12.5 and ZESTORETIC 20-25 were similar, suggesting that many patients who respond
adequately to the latter combination may be controlled with ZESTORETIC 20-12.5 (See
DOSAGE AND ADMINISTRATION).
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the
bioavailability of either drug.
The combination tablet is bioequivalent to concomitant
administration of the separate entities.
2
Reference ID: 3219425
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Lisinopril
Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE
is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor
substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal
cortex. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Removal of angiotensin II negative feedback on renin
secretion leads to increased plasma renin activity. In hypertensive patients with normal renal
function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium
was less than 0.1 mEq/L; however, approximately 15 percent of patients had increases greater
than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the
same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change
in serum potassium (See PRECAUTIONS).
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril
remains to be elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in
patients with low-renin hypertension. Although lisinopril was antihypertensive in all races
studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller
average response to lisinopril monotherapy than nonblack patients.
Pharmacokinetics and Metabolism:
Following oral administration of lisinopril, peak serum concentrations occur within about 7
hours. Declining serum concentrations exhibit a prolonged terminal phase which does not
contribute to drug accumulation. This terminal phase probably represents saturable binding to
ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum
proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based
on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with
large intersubject variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not
influenced by the presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
3
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Impaired renal function decreases elimination of lisinopril, which is excreted principally through
the kidneys, but this decrease becomes clinically important only when the glomerular filtration
rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little
changed. With greater impairment, however, peak and trough lisinopril levels increase, time to
peak concentration increases and time to attain steady state is prolonged. Older patients, on
average, have (approximately doubled) higher blood levels and area under the plasma
concentration
time
curve
(AUC)
than
younger
patients
(see
DOSAGE
AND
ADMINISTRATION).
In a multiple dose pharmacokinetic study in elderly versus young
hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased
approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older
patients. Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of
lisinopril in rats do not result in accumulation in any tissues; however, milk of lactating rats
contains radioactivity following administration of
14C lisinopril.
By whole body
autoradiography, radioactivity was found in the placenta following administration of labeled
drug to pregnant rats, but none was found in the fetuses.
Pharmacodynamics:
Administration of lisinopril to patients with hypertension results in a reduction of supine and
standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients (See WARNINGS).
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved
by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks
of therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24
hours, after dosing, although the effect at 24 hours was substantially smaller than the effect six
hours after dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt
withdrawal of lisinopril has not been associated with a rapid increase in blood pressure; nor with
a significant overshoot of pretreatment blood pressure.
4
Reference ID: 3219425
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In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac
output and in heart rate. In a study in nine hypertensive patients, following administration of
lisinopril, there was an increase in mean renal blood flow that was not significant. Data from
several small studies are inconsistent with respect to the effect of lisinopril on glomerular
filtration rate in hypertensive patients with normal renal function, but suggest that changes, if
any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and
effective in controlling blood pressure (See PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually
affect normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular
mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and
chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of
potassium and bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12
hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma
levels have been followed for at least 24 hours, the plasma half-life has been observed to vary
between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within
24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
INDICATIONS AND USAGE
ZESTORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes including lisinopril and hydrochlorothiazide.
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require
more than 1 drug to achieve blood pressure goals. For specific advice on goals and management,
see published guidelines, such as those of the National High Blood Pressure Education
Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
5
Reference ID: 3219425
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For current labeling information, please visit https://www.fda.gov/drugsatfda
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (eg,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND
ADMINISTRATION).
In using ZESTORETIC, consideration should be given to the fact that an angiotensin-converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal
impairment or collagen vascular disease, and that available data are insufficient to show that
lisinopril does not have a similar risk (See WARNINGS).
In considering the use of ZESTORETIC, it should be noted that ACE inhibitors have been
associated with a higher rate of angioedema in black than in nonblack patients (see
WARNINGS, Lisinopril).
CONTRAINDICATIONS
ZESTORETIC is contraindicated in patients who are hypersensitive to this product and in
patients
with
a
history
of
angioedema
related
to
previous
treatment
with
an
angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic
angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in
patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
WARNINGS
Lisinopril
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting
enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including ZESTORETIC) may be subject to a
variety of adverse reactions, some of them serious.
6
Reference ID: 3219425
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis
and/or larynx has been reported in patients treated with angiotensin-converting enzyme
inhibitors, including lisinopril. This may occur at any time during treatment. ACE inhibitors
have been associated with a higher rate of angioedema in black than in nonblack patients.
ZESTORETIC should be promptly discontinued and the appropriate therapy and monitoring
should be provided until complete and sustained resolution of signs and symptoms has occurred.
Even in those instances where swelling of only the tongue is involved, without respiratory
distress, patients may require prolonged observation since treatment with antihistamines and
corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to
angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the
tongue, glottis or larynx are likely to experience airway obstruction, especially those with a
history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely
to cause airway obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL)
and/or measures necessary to ensure a patent airway should be promptly provided (See
ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE
and CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization:
Two patients undergoing
desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-
threatening anaphylactoid reactions. In the same patients, these reactions were avoided when
ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure:
Thiazide-containing
combination products are not recommended in patients with severe renal dysfunction. Sudden
and potentially life-threatening anaphylactoid reactions have been reported in some patients
dialyzed with high-flux membranes (eg, AN69®*) and treated concomitantly with an ACE
inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for
anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in
these situations. In these patients, consideration should be given to using a different type of
dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have
also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
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Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated
hypertensive patients but is a possible consequence of lisinopril use in salt/volume-depleted
persons such as those treated vigorously with diuretics or patients on dialysis (See
PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).
Syncope has been reported in 0.8 percent of patients receiving ZESTORETIC. In patients with
hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall
incidence of syncope may be reduced by proper titration of the individual components (See
PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND
ADMINISTRATION).
In patients with severe congestive heart failure, with or without associated renal insufficiency,
excessive hypotension has been observed and may be associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood
pressure in these patients, therapy should be started under very close medical supervision. Such
patients should be followed closely for the first two weeks of treatment and whenever the dose of
lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic
heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a
myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary,
receive an intravenous infusion of normal saline. A transient hypotensive response is not a
contraindication to further doses which usually can be given without difficulty once the blood
pressure has increased after volume expansion.
Leukopenia/Neutropenia/Agranulocytosis:
Another angiotensin-converting enzyme
inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely
in uncomplicated patients but more frequently in patients with renal impairment, especially if
they also have a collagen vascular disease. Available data from clinical trials of lisinopril are
insufficient to show that lisinopril does not cause agranulocytosis at similar rates. Marketing
experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in
which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood
cell counts in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes)
death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors
who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE
inhibitor and receive appropriate medical follow-up.
Fetal Toxicity
Pregnancy category D
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Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue ZESTORETIC as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue ZESTORETIC, unless it is considered lifesaving for
the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
ZESTORETIC for hypotension, oliguria, and hyperkalemia. (see Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a
mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in
rabbits) the maximum recommended human dose.
Lisinopril and Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56
times the maximum recommended human dose) in combination with 10 mg/kg/day of
hydrochlorothiazide (2.5 times the maximum recommended human dose). Maternal or fetotoxic
effects were not seen in mice with the combination. In rats decreased maternal weight gain and
decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated
with the decreased fetal weight was a delay in fetal ossification. The decreased fetal weight and
delay in fetal ossification were not seen in saline-supplemented animals given 90/10 mg/kg/day.
When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause injury
and even death to the developing fetus. When pregnancy is detected, discontinue ZESTORETIC
as soon as possible (See Lisinopril, Fetal Toxicity).
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Hydrochlorothiazide
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a
sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute
angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain
and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure
glaucoma can lead to permanent vision loss. The primary treatment is to discontinue
hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to
be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute
angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Teratogenic Effects: Reproduction studies in the rabbit, the mouse and the rat at doses up to
100 mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the
fetus due to hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses
of 4-5.6 mg/kg/day (approximately 1-2 times the usual daily human dose) did not impair fertility
or produce birth abnormalities in the offspring. Thiazides cross the placental barrier and appear
in cord blood.
Nonteratogenic Effects: These may include fetal or neonatal jaundice, thrombocytopenia,
and possibly other adverse reactions have occurred in the adult.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with
impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive
liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic
coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial
asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (See PRECAUTIONS, Drug Interactions,
Lisinopril and Hydrochlorothiazide).
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy:
As with all vasodilators, lisinopril
should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
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Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the
renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors,
including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with
acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea
nitrogen and serum creatinine may occur. Experience with another angiotensin-converting
enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
lisinopril and/or diuretic therapy. In such patients renal function should be monitored during the
first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed
increases in blood urea and serum creatinine, usually minor and transient, especially when
lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients
with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the
diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function
(See DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L)
occurred in approximately 1.4 percent of hypertensive patients treated with lisinopril plus
hydrochlorothiazide. In most cases these were isolated values which resolved despite continued
therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant
use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt
substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. ZESTORETIC
should be used cautiously, if at all, with these agents and with frequent monitoring of serum
potassium (See PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent nonproductive cough has been reported with all ACE inhibitors, almost always
resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered
in the differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, lisinopril may block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to this
mechanism, it can be corrected by volume expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
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All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or
receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance,
irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or
after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of
the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Because lisinopril
reduces the production of aldosterone, concomitant therapy with lisinopril attenuates the diuretic-
induced potassium loss (See PRECAUTIONS, Drug Interactions, Agents Increasing Serum
Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment,
except under extraordinary circumstances (as in liver disease or renal disease), chloride
replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is
water restriction, rather than administration of salt except in rare instances when the
hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy
of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become
manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic
therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
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Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight
elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked
hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be
discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including laryngeal edema may occur at any time during
treatment with angiotensin-converting enzyme inhibitors, including ZESTORETIC. Patients
should be so advised and told to report immediately any signs or symptoms suggesting
angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or
breathing) and to take no more drug until they have consulted with the prescribing physician.
Symptomatic Hypotension:
Patients should be cautioned to report lightheadedness
especially during the first few days of therapy. If actual syncope occurs, the patients should be
told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an
excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume
depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should
be advised to consult with their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of
infection (eg, sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ZESTORETIC during pregnancy. Discuss treatment options with women planning to
become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
NOTE: As with many other drugs, certain advice to patients being treated with ZESTORETIC
is warranted. This information is intended to aid in the safe and effective use of this medication.
It is not a disclosure of all possible adverse or intended effects.
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Drug Interactions
Lisinopril
Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in
whom diuretic therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with lisinopril. The possibility of
hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or
increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to
continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close
medical supervision after the initial dose for at least two hours and until blood pressure has
stabilized for at least an additional hour (See WARNINGS, and DOSAGE AND
ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril,
an additional antihypertensive effect is usually observed
(See DOSAGE AND
ADMINISTRATION).
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors
(COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic
therapy), or with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with ACE inhibitors, including lisinopril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving lisinopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by
NSAIDs.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is
associated with increased risks of hypotension, hyperkalemia, and changes in renal function
(including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal
function and electrolytes in patients on ZESTORETIC and other agents that affect the RAS.
Do not co-administer aliskiren with ZESTORETIC in patients with diabetes. Avoid use of
aliskiren with ZESTORETIC in patients with renal impairment (GFR < 60 ml/min).
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without
evidence of clinically significant adverse interactions. No meaningful clinically important
pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol,
digoxin, or hydrochlorothiazide. The presence of food in the stomach does not alter the
bioavailability of lisinopril.
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Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide
type diuretics.
Use of lisinopril with potassium-sparing diuretics (eg, spironolactone,
eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt
substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use
of these agents is indicated, because of demonstrated hypokalemia, they should be used with
caution and with frequent monitoring of serum potassium.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with
drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was
usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended
that serum lithium levels be monitored frequently if lisinopril is administered concomitantly with
lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may
be required.
Other antihypertensive drugs - additive effect or potentiation.
Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85
and 43 percent, respectively.
Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (eg, norepinephrine) - possible decreased response to pressor amines but not
sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine) -
possible increased
responsiveness to the muscle relaxant.
Lithium - should not generally be given with diuretics. Diuretic agents reduce the renal
clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for
lithium preparations before use of such preparations with ZESTORETIC.
Non-Steroidal Anti-inflammatory Drugs - In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive
effects of loop, potassium-sparing and thiazide diuretics. Therefore, when ZESTORETIC and
non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed
closely to determine if the desired effect of ZESTORETIC is obtained.
Reference ID: 3219425
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Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy including ZESTORETIC.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril and Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen
test using Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic
activation or in a forward mutation assay using Chinese hamster lung cells. Lisinopril and
hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution rat
hepatocyte assay. In addition, it did not produce increases in chromosomal aberrations in an in
vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks
to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily
human dose, based on body weight and body surface area, respectively). There was no evidence
of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at
doses up to 135 mg/kg/day (about 84 times*
the maximum recommended daily human dose). This dose was 6.8 times the maximum human
dose based on body surface area in mice.
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic
activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte
assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro
test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with
up to 300 mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily
human dose based on mg/kg and mg/m2, respectively.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male
and female rats (at doses of up to approximately 100 mg/kg/day). These doses are 150 times and
12 times for mice and 25 times and 4 times for rats the maximum human daily dose based on
mg/kg and mg/m2, respectively. The NTP, however, found equivocal evidence for
hepatocarcinogenicity in male mice.
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Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse
germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila
sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO
Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity)
assays, using concentrations of hydrochlorothiazide from 43 to 1300 g/mL, and in the
Aspergillus nidulans nondisjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg,
respectively, prior to conception and throughout gestation. In mice this dose is 25 times and
2 times the maximum daily human dose based on mg/kg and mg/m2, respectively. In rats this
dose is 1 times and 0.2 times the maximum daily human dose based on mg/kg and mg/m2,
respectively.
Nursing Mothers
It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats
contains radioactivity following administration of 14C lisinopril. In another study, lisinopril was
present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human
milk. Because of the potential for serious adverse reactions in nursing infants from ACE
inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing
and/or discontinue ZESTORETIC, taking into account the importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to ZESTORETIC:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion.
Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the
placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical
benefit, and theoretically may be removed by exchange transfusion, although there is no
experience with the latter procedure.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of ZESTORETIC did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
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This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection. Evaluation
of the hypertensive patient should always include assessment of renal function.
ADVERSE REACTIONS
ZESTORETIC has been evaluated for safety in 930 patients including 100 patients treated for 50
weeks or more.
In clinical trials with ZESTORETIC no adverse experiences peculiar to this combination drug
have been observed. Adverse experiences that have occurred have been limited to those that
have been previously reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label
extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5%),
headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were
more common than in placebo-treated patients. Generally, adverse experiences were mild and
transient in nature, but see WARNINGS regarding angioedema and excessive hypotension or
syncope. Discontinuation of therapy due to adverse effects was required in 4.4% of patients
principally because of dizziness, cough, fatigue and muscle cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies
Lisinopril and
Hydrochlorothiazide
(n=930)
Incidence
(discontinuation)
Placebo
(n=207)
Incidence
Dizziness
7.5
(0.8)
1.9
Headache
5.2
(0.3)
1.9
Cough
3.9
(0.6)
1.0
Fatigue
3.7
(0.4)
1.0
Orthostatic Effects
3.2
(0.1)
1.0
Diarrhea
2.5
(0.2)
2.4
Nausea
2.2
(0.1)
2.4
Upper Respiratory Infection
2.2
(0.0)
0.0
Muscle Cramps
2.0
(0.4)
0.5
Asthenia
1.8
(0.2)
1.0
Paresthesia
1.5
(0.1)
0.0
Hypotension
1.4
(0.3)
0.5
Vomiting
1.4
(0.1)
0.5
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Dyspepsia
1.3
(0.0)
0.0
Rash
1.2
(0.1)
0.5
Impotence
1.2
(0.3)
0.0
Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer,
serious, possibly drug-related events reported in marketing experience are listed below:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus
infection. Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal
cramps, dry mouth, constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee
pain, back strain, myalgia, foot pain. Nervous/Psychiatric: Decreased libido, vertigo,
depression, somnolence. Respiratory: Common cold, nasal congestion, influenza, bronchitis,
pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal
discomfort. Skin:
Flushing, pruritus, skin inflammation, diaphoresis, cutaneous
pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract
infection.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been
reported (See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows:
hypotension (1.4%), orthostatic hypotension (0.5%), other orthostatic effects (3.2%). In addition
syncope occurred in 0.8% of patients (See WARNINGS).
Cough: See PRECAUTIONS - Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: (See PRECAUTIONS).
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum
creatinine were observed in patients with essential hypertension treated with ZESTORETIC.
More marked increases have also been reported and were more likely to occur in patients with
renal artery stenosis (See PRECAUTIONS).
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See
PRECAUTIONS).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases
of approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive
patients treated with ZESTORETIC but were rarely of clinical importance unless another cause
of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred
(See WARNINGS, Hepatic Failure).
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Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with
ZESTORETIC. In addition, and since lisinopril has been marketed, the following adverse
reactions have been reported with lisinopril and should be considered potential adverse reactions
for ZESTORETIC:
Body as a Whole: Anaphylactoid reactions (see WARNINGS,
Anaphylactoid Reactions During Membrane Exposure), malaise, edema, facial edema, pain,
pelvic pain, flank pain, chills; Cardiovascular: Cardiac arrest, myocardial infarction or
cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see
WARNINGS, Hypotension), pulmonary embolism and infarction, worsening of heart failure,
arrhythmias (including tachycardia, ventricular tachycardia, atrial tachycardia, atrial fibrillation,
bradycardia, and premature ventricular contractions), angina pectoris, transient ischemic attacks,
paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema, vasculitis;
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes
mellitus, inappropriate antidiuretic hormone secretion; Hematologic: Rare cases of bone
marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been
reported in which a causal relationship to lisinopril can not be excluded; Metabolic: Gout,
weight loss, dehydration, fluid overload, weight gain;
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain,
lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (eg, paresthesia, dysesthesia), spasm,
hypersomnia, irritability; mood alterations (including depressive symptoms); Respiratory:
Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm,
asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful
respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound
abnormalities; Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin
infections, pemphigus, erythema, psoriasis, rare cases of other severe skin reactions, including
toxic epidermal necrolysis and Stevens-Johnson Syndrome (causal relationship has not been
established); Special Senses: Visual loss, diplopia, photophobia, taste alteration, olfactory
disturbance; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive azotemia,
renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),
pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis,
eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations
may occur alone or in combination with these symptoms.
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Hydrochlorothiazide - Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation,
cramping, jaundice (intrahepatic cholestatic jaundice) (See WARNINGS, Hepatic Failure),
pancreatitis,
sialoadenitis,
constipation;
Hematologic:
Leukopenia,
agranulocytosis,
thrombocytopenia, aplastic anemia, hemolytic anemia; Musculoskeletal: Muscle spasm;
Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial
nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson Syndrome,
exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses:
Xanthopsia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis
(vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary
edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with ZESTORETIC.
Treatment is symptomatic and supportive. Therapy with ZESTORETIC should be discontinued
and the patient observed closely. Suggested measures include induction of emesis and/or gastric
lavage, and correction of dehydration, electrolyte imbalance and hypotension by established
procedures.
Lisinopril
Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of
20 mice receiving the same dose. The most likely manifestation of overdosage would be
hypotension, for which the usual treatment would be intravenous infusion of normal saline
solution.
Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During
Membrane Exposure).
Hydrochlorothiazide
Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most
common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia,
hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has
also been administered, hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80
mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 - 50 mg per day. In
clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of
10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates
generally increased with increasing dose of either component.
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The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of
dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily
hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more
common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide
may be associated with either or both dose-independent or dose-dependent side effects, but
addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy
only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately
controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to
lisinopril/HCTZ 10/12.5 or lisinopril/HCTZ 20/12.5, depending on current monotherapy dose.
Further increases of either or both components should depend on clinical response with blood
pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive
effect at that time. The hydrochlorothiazide dose should generally not be increased until 2-3
weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of
lisinopril.
Patients whose blood pressures are adequately controlled with 25 mg of daily
hydrochlorothiazide, but who experience significant potassium loss with this regimen may
achieve similar or greater blood-pressure control without electrolyte disturbance if they are
switched to lisinopril/HCTZ 10/12.5.
In patients who are currently being treated with a diuretic, symptomatic hypotension
occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible,
be discontinued for two to three days before beginning therapy with lisinopril to reduce the
likelihood of hypotension (See WARNINGS). If the patient's blood pressure is not controlled
with lisinopril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under
medical supervision for at least two hours and until blood pressure has stabilized for at least an
additional hour (See WARNINGS and PRECAUTIONS, Drug Interactions).
Concomitant administration of ZESTORETIC with potassium supplements, potassium salt
substitutes or potassium-sparing diuretics may lead to increases of serum potassium (See
PRECAUTIONS).
Replacement Therapy: The combination may be substituted for the titrated individual
components.
Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of
renal function as long as the patient's creatinine clearance is >30 mL/min/1.7m2 (serum creatinine
roughly 3 mg/dL or 265 mol/L). In patients with more severe renal impairment, loop diuretics
are preferred to thiazides, so lisinopril/HCTZ is not recommended (see WARNINGS,
Anaphylactoid Reactions During Membrane Exposure).
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HOW SUPPLIED
ZESTORETIC 10-12.5 Tablets (NDC 0310-0141) Peach, round, biconvex, uncoated tablets
identified with "141" debossed on one side and "ZESTORETIC" on the other side are supplied in
bottles of 100 tablets.
ZESTORETIC 20-12.5 Tablets (NDC 0310-0142) White, round, biconvex, uncoated tablets
identified with "142" debossed on one side and "ZESTORETIC" on the other side are supplied
in bottles of 100 tablets.
ZESTORETIC 20-25 Tablets (NDC 0310-0145) Peach, round, biconvex, uncoated tablets
identified with “145” debossed on one side and "ZESTORETIC" on the other side are supplied in
bottles of 100 tablets.
Storage
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from excessive
light and humidity.
*AN69 is a registered trademark of Hospal Ltd.
ZESTORETIC is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2012
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Revision: October 2012
AstraZeneca
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019888s053lbl.pdf', 'application_number': 19888, 'submission_type': 'SUPPL ', 'submission_number': 53}
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ZESTORETIC®
(lisinopril and hydrochlorothiazide)
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue ZESTORETIC as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. See Warnings: Fetal Toxicity.
DESCRIPTION
ZESTORETIC® (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme
inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor.
It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its
empirical formula is C21H31N3O5 . 2H2O and its structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in
water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is C7H8ClN3O4S2 and its structural formula is:
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of
297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
ZESTORETIC is available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide:
ZESTORETIC 10-12.5 containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide; ZESTORETIC 20
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12.5 containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and, ZESTORETIC 20-25 containing
20 mg lisinopril and 25 mg hydrochlorothiazide.
Inactive Ingredients:
10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, starch.
20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
CLINICAL PHARMACOLOGY
Lisinopril and Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases
aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the renin
angiotensin aldosterone axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and
hydrochlorothiazide was approximately additive. The ZESTORETIC 10-12.5 combination worked
equally well in black and white patients. The ZESTORETIC 20-12.5 and ZESTORETIC 20-25
combinations appeared somewhat less effective in black patients, but relatively few black patients were
studied. In most patients, the antihypertensive effect of ZESTORETIC was sustained for at least 24
hours.
In a randomized, controlled comparison, the mean antihypertensive effects of ZESTORETIC 20-12.5 and
ZESTORETIC 20-25 were similar, suggesting that many patients who respond adequately to the latter
combination may be controlled with ZESTORETIC 20-12.5 (See DOSAGE AND
ADMINISTRATION).
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the
bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of
the separate entities.
Lisinopril
Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of
ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to
decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the
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mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of
patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than
0.5 mEq/L. In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially
no change in serum potassium (See PRECAUTIONS).
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be
elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients
with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, black
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
lisinopril monotherapy than nonblack patients.
Pharmacokinetics and Metabolism:
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours.
Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug
accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional
to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary
recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject
variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the
presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients (see
DOSAGE AND ADMINISTRATION). In a multiple dose pharmacokinetic study in elderly versus
young hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased
approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues; however, milk of lactating rats contains radioactivity
following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the
placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
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Pharmacodynamics:
Administration of lisinopril to patients with hypertension results in a reduction of supine and standing
blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural
hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-
depleted patients (See WARNINGS).
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration
of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours,
after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after
dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of
lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot
of pretreatment blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in
controlling blood pressure (See PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect
normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of
electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in
approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and
bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have
been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8
hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide
crosses the placental but not the blood-brain barrier.
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INDICATIONS AND USAGE
ZESTORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood
pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial
infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide
variety of pharmacologic classes including lisinopril and hydrochlorothiazide.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,
exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood
pressure goals. For specific advice on goals and management, see published guidelines, such as those of
the National High Blood Pressure Education Program’s Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other
pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most
consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in
myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase
per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can
provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across
populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk
independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such
patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and
many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart
failure, or diabetic kidney disease). These considerations may guide selection of therapy.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND
ADMINISTRATION).
In using ZESTORETIC, consideration should be given to the fact that an angiotensin-converting enzyme
inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen
vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk
(See WARNINGS).
In considering the use of ZESTORETIC, it should be noted that ACE inhibitors have been associated with
a higher rate of angioedema in black than in nonblack patients (see WARNINGS, Lisinopril).
CONTRAINDICATIONS
ZESTORETIC is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this
product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
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Do not co-administer aliskiren with ZESTORETIC in patients with diabetes (see PRECAUTIONS, Drug
Interactions).
WARNINGS
Lisinopril
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme
inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including ZESTORETIC) may be subject to a variety of adverse
reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This
may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in black than in nonblack patients. ZESTORETIC should be promptly discontinued and the
appropriate therapy and monitoring should be provided until complete and sustained resolution of signs
and symptoms has occurred. Even in those instances where swelling of only the tongue is involved,
without respiratory distress, patients may require prolonged observation since treatment with
antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to
angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue,
glottis or larynx are likely to experience airway obstruction, especially those with a history of airway
surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway
obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures
necessary to ensure a patent airway should be promptly provided (See ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there
was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was
diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms
resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with
hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.
In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but
they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Thiazide-containing combination products are
not recommended in patients with severe renal dysfunction. Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (eg,
AN69®*) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not
been relieved by antihistamines in these situations. In these patients, consideration should be given to
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using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid
reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive
patients but is a possible consequence of lisinopril use in salt/volume-depleted persons such as those
treated vigorously with diuretics or patients on dialysis (See PRECAUTIONS, Drug Interactions and
ADVERSE REACTIONS).
Syncope has been reported in 0.8 percent of patients receiving ZESTORETIC. In patients with
hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence
of syncope may be reduced by proper titration of the individual components (See PRECAUTIONS, Drug
Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive
hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and
rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these
patients, therapy should be started under very close medical supervision. Such patients should be
followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is
increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in
whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular
accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an
intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to
further doses which usually can be given without difficulty once the blood pressure has increased after
volume expansion.
Leukopenia/Neutropenia/Agranulocytosis: Another angiotensin-converting enzyme inhibitor, captopril,
has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients
but more frequently in patients with renal impairment, especially if they also have a collagen vascular
disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not
cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be
excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and
renal disease should be considered.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice
or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate
medical follow-up.
Fetal Toxicity
Pregnancy category D
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Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential
neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When
pregnancy is detected, discontinue ZESTORETIC as soon as possible. These adverse outcomes are
usually associated with use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first
trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive
agents. Appropriate management of maternal hypertension during pregnancy is important to optimize
outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin
angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform
serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,
discontinue ZESTORETIC, unless it is considered lifesaving for the mother. Fetal testing may be
appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe
infants with histories of in utero exposure to ZESTORETIC for hypotension, oliguria, and hyperkalemia.
(see Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg
basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the
maximum recommended human dose.
Lisinopril and Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56 times the
maximum recommended human dose) in combination with 10 mg/kg/day of hydrochlorothiazide (2.5
times the maximum recommended human dose). Maternal or fetotoxic effects were not seen in mice with
the combination. In rats decreased maternal weight gain and decreased fetal weight occurred down to
3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was a delay in fetal
ossification. The decreased fetal weight and delay in fetal ossification were not seen in saline-
supplemented animals given 90/10 mg/kg/day.
When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause injury and
even death to the developing fetus. When pregnancy is detected, discontinue ZESTORETIC as soon as
possible (See Lisinopril, Fetal Toxicity).
Hydrochlorothiazide
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can
cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours
to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk
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factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin
allergy.
Teratogenic Effects: Reproduction studies in the rabbit, the mouse and the rat at doses up to 100
mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the fetus due to
hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses of 4-5.6 mg/kg/day
(approximately 1-2 times the usual daily human dose) did not impair fertility or produce birth
abnormalities in the offspring. Thiazides cross the placental barrier and appear in cord blood.
Nonteratogenic Effects: These may include fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions have occurred in the adult.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides
may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal
function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (See PRECAUTIONS, Drug Interactions, Lisinopril
and Hydrochlorothiazide).
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given
with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe
congestive heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including lisinopril, may be
associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen
and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor
suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic
therapy. In such patients renal function should be monitored during the first few weeks of therapy.
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Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases
in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function (See
DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In
most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a
cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium
supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes
fatal, arrhythmias. ZESTORETIC should be used cautiously, if at all, with these agents and with frequent
monitoring of serum potassium (See PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, almost always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce
hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If
hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume
expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed
at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or receiving
parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause,
include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after
prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may
cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic
effects of digitalis (eg, increased ventricular irritability). Because lisinopril reduces the production of
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aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (See
PRECAUTIONS, Drug Interactions, Agents Increasing Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment, except
under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be
required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water
restriction, rather than administration of salt except in rare instances when the hyponatremia is life-
threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest
during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation
of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may
be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment with
angiotensin-converting enzyme inhibitors, including ZESTORETIC. Patients should be so advised and
told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities,
eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have
consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the
first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall
in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as
vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with
their physician.
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Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to
ZESTORETIC during pregnancy. Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with ZESTORETIC is
warranted. This information is intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Drug Interactions
Lisinopril
Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril
can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a
dose of 5 mg daily, and provide close medical supervision after the initial dose for at least two hours and
until blood pressure has stabilized for at least an additional hour (See WARNINGS, and DOSAGE AND
ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril, an
additional antihypertensive effect is usually observed (See DOSAGE AND ADMINISTRATION).
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute
renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving lisinopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is
associated with increased risks of hypotension, hyperkalemia, and changes in renal function
(including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal
function and electrolytes in patients on ZESTORETIC and other agents that affect the RAS.
Do not co-administer aliskiren with ZESTORETIC in patients with diabetes. Avoid use of
aliskiren with ZESTORETIC in patients with renal impairment (GFR < 60 ml/min).
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. No meaningful clinically important pharmacokinetic
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interactions occurred when lisinopril was used concomitantly with propranolol, digoxin, or
hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type
diuretics. Use of lisinopril with potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene,
or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant
increases in serum potassium. Therefore, if concomitant use of these agents is indicated, because of
demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum
potassium.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs
which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible
upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be
monitored frequently if lisinopril is administered concomitantly with lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be
required.
Other antihypertensive drugs - additive effect or potentiation.
Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the
hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (eg, norepinephrine) - possible decreased response to pressor amines but not sufficient
to preclude their use.
Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine) - possible increased responsiveness to
the muscle relaxant.
Lithium - should not generally be given with diuretics. Diuretic agents reduce the renal clearance of
lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before
use of such preparations with ZESTORETIC.
Non-Steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-
inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-
sparing and thiazide diuretics. Therefore, when ZESTORETIC and non-steroidal anti-inflammatory
agents are used concomitantly, the patient should be observed closely to determine if the desired effect of
ZESTORETIC is obtained.
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Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have
been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant
ACE inhibitor therapy including ZESTORETIC.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril and Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using
Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a
forward mutation assay using Chinese hamster lung cells. Lisinopril and hydrochlorothiazide did not
produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, it did
not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in
an in vivo study in mouse bone marrow.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male
and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily human dose, based
on body weight and body surface area, respectively). There was no evidence of carcinogenicity when
lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about
84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human
dose based on body surface area in mice.
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2 .
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It
was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition,
lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster
ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to 300
mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily human dose based on
mg/kg and mg/m2, respectively.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology
Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice
(at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to
approximately 100 mg/kg/day). These doses are 150 times and 12 times for mice and 25 times and 4
times for rats the maximum human daily dose based on mg/kg and mg/m2, respectively. The NTP,
however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary
(CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes,
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Reference ID: 3401765
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Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.
Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity)
and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
from 43 to 1300 μg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified
concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies
wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior
to conception and throughout gestation. In mice this dose is 25 times and 2 times the maximum daily
human dose based on mg/kg and mg/m2, respectively. In rats this dose is 1 times and 0.2 times the
maximum daily human dose based on mg/kg and mg/m2, respectively.
Nursing Mothers
It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains
radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk
at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the
potential for serious adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a
decision should be made whether to discontinue nursing and/or discontinue ZESTORETIC, taking into
account the importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to ZESTORETIC:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or
substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from
neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed
by exchange transfusion, although there is no experience with the latter procedure.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of ZESTORETIC did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience has
not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function.
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ADVERSE REACTIONS
ZESTORETIC has been evaluated for safety in 930 patients including 100 patients treated for 50 weeks
or more.
In clinical trials with ZESTORETIC no adverse experiences peculiar to this combination drug have been
observed. Adverse experiences that have occurred have been limited to those that have been previously
reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with
any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5%), headache (5.2%), cough
(3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were more common than in placebo-
treated patients. Generally, adverse experiences were mild and transient in nature, but see WARNINGS
regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse
effects was required in 4.4% of patients principally because of dizziness, cough, fatigue and muscle
cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies
Lisinopril and Hydrochlorothiazide (n=930)
Placebo (n=207)
Incidence (discontinuation)
Incidence
Dizziness
7.5
(0.8)
1.9
Headache
5.2
(0.3)
1.9
Cough
3.9
(0.6)
1.0
Fatigue
3.7
(0.4)
1.0
Orthostatic Effects
3.2
(0.1)
1.0
Diarrhea
2.5
(0.2)
2.4
Nausea
2.2
(0.1)
2.4
Upper Respiratory
2.2
(0.0)
0.0
Infection
Muscle Cramps
2.0
(0.4)
0.5
Asthenia
1.8
(0.2)
1.0
Paresthesia
1.5
(0.1)
0.0
Hypotension
1.4
(0.3)
0.5
Vomiting
1.4
(0.1)
0.5
Dyspepsia
1.3
(0.0)
0.0
Rash
1.2
(0.1)
0.5
Impotence
1.2
(0.3)
0.0
Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer, serious,
possibly drug-related events reported in marketing experience are listed below:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.
Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth,
constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia,
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foot pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory:
Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion,
chronic sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation,
diaphoresis, cutaneous pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital:
Urinary tract infection.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported
(See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension
(1.4%), orthostatic hypotension (0.5%), other orthostatic effects (3.2%). In addition syncope occurred in
0.8% of patients (See WARNINGS).
Cough: See PRECAUTIONS - Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: (See PRECAUTIONS).
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum
creatinine were observed in patients with essential hypertension treated with ZESTORETIC. More
marked increases have also been reported and were more likely to occur in patients with renal artery
stenosis (See PRECAUTIONS).
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See
PRECAUTIONS).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive patients treated
with ZESTORETIC but were rarely of clinical importance unless another cause of anemia coexisted. In
clinical trials, 0.4% of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See
WARNINGS, Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with
ZESTORETIC. In addition, and since lisinopril has been marketed, the following adverse reactions have
been reported with lisinopril and should be considered potential adverse reactions for ZESTORETIC:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;
Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high risk patients (see WARNINGS, Hypotension), pulmonary embolism and
infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris,
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transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema,
vasculitis; Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus,
inappropriate antidiuretic hormone secretion; Hematologic: Rare cases of bone marrow depression,
hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported in which a causal
relationship to lisinopril can not be excluded; Metabolic: Gout, weight loss, dehydration, fluid overload,
weight gain; Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain,
lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (eg, paresthesia, dysesthesia), spasm, hypersomnia,
irritability; mood alterations (including depressive symptoms); hallucinations; Respiratory: Malignant
lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural
effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful respiration, epistaxis,
laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities; Skin: Urticaria, alopecia,
herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, psoriasis, rare cases
of other severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome
(causal relationship has not been established); Special Senses: Visual loss, diplopia, photophobia, taste
alteration, olfactory disturbance; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive
azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),
pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated
erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Hydrochlorothiazide - Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping,
jaundice (intrahepatic cholestatic jaundice) (See WARNINGS, Hepatic Failure), pancreatitis,
sialoadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic
anemia, hemolytic anemia; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric:
Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin:
Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic
epidermal necrolysis, alopecia; Special Senses: Xanthopsia; Hypersensitivity: Purpura,
photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress
including pneumonitis and pulmonary edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with ZESTORETIC. Treatment is
symptomatic and supportive. Therapy with ZESTORETIC should be discontinued and the patient
observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction
of dehydration, electrolyte imbalance and hypotension by established procedures.
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Lisinopril
Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of 20 mice
receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which
the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During
Membrane Exposure).
Hydrochlorothiazide
Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most common
signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia,
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide monotherapy is effective in doses of 12.5 - 50 mg per day. In clinical trials of
lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and
hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with
increasing dose of either component.
The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose;
those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and
dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy
with any combination of lisinopril and hydrochlorothiazide may be associated with either or both dose-
independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the
hypokalemia normally seen with diuretics.
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy only after
a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled
with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril/HCTZ 10/12.5 or
lisinopril/HCTZ 20/12.5, depending on current monotherapy dose. Further increases of either or both
components should depend on clinical response with blood pressure measured at the interdosing interval
to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose
should generally not be increased until 2-3 weeks have elapsed. After addition of the diuretic it may be
possible to reduce the dose of lisinopril. Patients whose blood pressures are adequately controlled with
25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen may
achieve similar or greater blood-pressure control without electrolyte disturbance if they are switched to
lisinopril/HCTZ 10/12.5.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may
occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to
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three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (See
WARNINGS). If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may
be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour
(See WARNINGS and PRECAUTIONS, Drug Interactions).
Concomitant administration of ZESTORETIC with potassium supplements, potassium salt substitutes or
potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).
Replacement Therapy: The combination may be substituted for the titrated individual components.
Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of renal
function as long as the patient's creatinine clearance is >30 mL/min/1.7m2 (serum creatinine roughly ≤3
mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to
thiazides, so lisinopril/HCTZ is not recommended (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure).
HOW SUPPLIED
ZESTORETIC 10-12.5 Tablets (NDC 0310-0141) Peach, round, biconvex, uncoated tablets identified
with "141" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
ZESTORETIC 20-12.5 Tablets (NDC 0310-0142) White, round, biconvex, uncoated tablets identified
with "142" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
ZESTORETIC 20-25 Tablets (NDC 0310-0145) Peach, round, biconvex, uncoated tablets identified
with “145” debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
Storage
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from excessive light and
humidity.
*AN69 is a registered trademark of Hospal Ltd.
ZESTORETIC is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2012
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Revision: 11/2013
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019888s055lbl.pdf', 'application_number': 19888, 'submission_type': 'SUPPL ', 'submission_number': 55}
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ZESTORETIC®
(lisinopril and hydrochlorothiazide)
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue ZESTORETIC as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. See Warnings: Fetal Toxicity.
DESCRIPTION
ZESTORETIC® (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme
inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor.
It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its
empirical formula is C21H31N3O5 . 2H2O and its structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in
water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is C7H8ClN3O4S2 and its structural formula is:
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of
297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
ZESTORETIC is available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide:
ZESTORETIC 10-12.5 containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide; ZESTORETIC 20-
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12.5 containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and, ZESTORETIC 20-25 containing
20 mg lisinopril and 25 mg hydrochlorothiazide.
Inactive Ingredients:
10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, starch.
20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
CLINICAL PHARMACOLOGY
Lisinopril and Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases
aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the renin-
angiotensin aldosterone axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and
hydrochlorothiazide was approximately additive. The ZESTORETIC 10-12.5 combination worked
equally well in black and white patients. The ZESTORETIC 20-12.5 and ZESTORETIC 20-25
combinations appeared somewhat less effective in black patients, but relatively few black patients were
studied. In most patients, the antihypertensive effect of ZESTORETIC was sustained for at least 24
hours.
In a randomized, controlled comparison, the mean antihypertensive effects of ZESTORETIC 20-12.5 and
ZESTORETIC 20-25 were similar, suggesting that many patients who respond adequately to the latter
combination may be controlled with ZESTORETIC 20-12.5 (See DOSAGE AND
ADMINISTRATION).
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the
bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of
the separate entities.
Lisinopril
Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of
ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to
decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the
mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of
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patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than
0.5 mEq/L. In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially
no change in serum potassium (See PRECAUTIONS).
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be
elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients
with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, black
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
lisinopril monotherapy than nonblack patients.
Pharmacokinetics and Metabolism:
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours.
Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug
accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional
to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary
recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject
variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the
presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients (see
DOSAGE AND ADMINISTRATION). In a multiple dose pharmacokinetic study in elderly versus
young hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased
approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues; however, milk of lactating rats contains radioactivity
following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the
placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pharmacodynamics:
Administration of lisinopril to patients with hypertension results in a reduction of supine and standing
blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural
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hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-
depleted patients (See WARNINGS).
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration
of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours,
after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after
dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of
lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot
of pretreatment blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in
controlling blood pressure (See PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect
normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of
electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in
approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and
bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have
been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8
hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide
crosses the placental but not the blood-brain barrier.
INDICATIONS AND USAGE
ZESTORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood
pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial
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infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide
variety of pharmacologic classes including lisinopril and hydrochlorothiazide.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,
exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood
pressure goals. For specific advice on goals and management, see published guidelines, such as those of
the National High Blood Pressure Education Program’s Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other
pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most
consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in
myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase
per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can
provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across
populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk
independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such
patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and
many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart
failure, or diabetic kidney disease). These considerations may guide selection of therapy.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND
ADMINISTRATION).
In using ZESTORETIC, consideration should be given to the fact that an angiotensin-converting enzyme
inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen
vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk
(See WARNINGS).
In considering the use of ZESTORETIC, it should be noted that ACE inhibitors have been associated with
a higher rate of angioedema in black than in nonblack patients (see WARNINGS, Lisinopril).
CONTRAINDICATIONS
ZESTORETIC is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this
product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with ZESTORETIC in patients with diabetes (see PRECAUTIONS, Drug
Interactions).
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WARNINGS
Lisinopril
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme
inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including ZESTORETIC) may be subject to a variety of adverse
reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This
may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in black than in nonblack patients. ZESTORETIC should be promptly discontinued and the
appropriate therapy and monitoring should be provided until complete and sustained resolution of signs
and symptoms has occurred. Even in those instances where swelling of only the tongue is involved,
without respiratory distress, patients may require prolonged observation since treatment with
antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to
angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue,
glottis or larynx are likely to experience airway obstruction, especially those with a history of airway
surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway
obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures
necessary to ensure a patent airway should be promptly provided (See ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there
was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was
diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms
resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with
hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.
In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but
they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Thiazide-containing combination products are
not recommended in patients with severe renal dysfunction. Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (eg,
AN69®*) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not
been relieved by antihistamines in these situations. In these patients, consideration should be given to
using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid
reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
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Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive
patients but is a possible consequence of lisinopril use in salt/volume-depleted persons such as those
treated vigorously with diuretics or patients on dialysis (See PRECAUTIONS, Drug Interactions and
ADVERSE REACTIONS).
Syncope has been reported in 0.8 percent of patients receiving ZESTORETIC. In patients with
hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence
of syncope may be reduced by proper titration of the individual components (See PRECAUTIONS, Drug
Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive
hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and
rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these
patients, therapy should be started under very close medical supervision. Such patients should be
followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is
increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in
whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular
accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an
intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to
further doses which usually can be given without difficulty once the blood pressure has increased after
volume expansion.
Leukopenia/Neutropenia/Agranulocytosis: Another angiotensin-converting enzyme inhibitor, captopril,
has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients
but more frequently in patients with renal impairment, especially if they also have a collagen vascular
disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not
cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be
excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and
renal disease should be considered.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice
or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate
medical follow-up.
Fetal Toxicity
Pregnancy category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential
neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When
pregnancy is detected, discontinue ZESTORETIC as soon as possible. These adverse outcomes are
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usually associated with use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first
trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive
agents. Appropriate management of maternal hypertension during pregnancy is important to optimize
outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-
angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform
serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,
discontinue ZESTORETIC, unless it is considered lifesaving for the mother. Fetal testing may be
appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe
infants with histories of in utero exposure to ZESTORETIC for hypotension, oliguria, and hyperkalemia.
(see Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg
basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the
maximum recommended human dose.
Lisinopril and Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56 times the
maximum recommended human dose) in combination with 10 mg/kg/day of hydrochlorothiazide (2.5
times the maximum recommended human dose). Maternal or fetotoxic effects were not seen in mice with
the combination. In rats decreased maternal weight gain and decreased fetal weight occurred down to
3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was a delay in fetal
ossification. The decreased fetal weight and delay in fetal ossification were not seen in saline-
supplemented animals given 90/10 mg/kg/day.
When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause injury and
even death to the developing fetus. When pregnancy is detected, discontinue ZESTORETIC as soon as
possible (See Lisinopril, Fetal Toxicity).
Hydrochlorothiazide
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can
cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours
to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk
factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin
allergy.
Teratogenic Effects: Reproduction studies in the rabbit, the mouse and the rat at doses up to 100
mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the fetus due to
hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses of 4-5.6 mg/kg/day
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(approximately 1-2 times the usual daily human dose) did not impair fertility or produce birth
abnormalities in the offspring. Thiazides cross the placental barrier and appear in cord blood.
Nonteratogenic Effects: These may include fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions have occurred in the adult.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides
may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal
function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (See PRECAUTIONS, Drug Interactions, Lisinopril
and Hydrochlorothiazide).
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given
with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe
congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-
aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including lisinopril, may be
associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen
and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor
suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic
therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases
in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function (See
DOSAGE AND ADMINISTRATION).
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Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In
most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a
cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium
supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes
fatal, arrhythmias. ZESTORETIC should be used cautiously, if at all, with these agents and with frequent
monitoring of serum potassium (See PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, almost always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce
hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If
hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume
expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed
at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or receiving
parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause,
include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after
prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may
cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic
effects of digitalis (eg, increased ventricular irritability). Because lisinopril reduces the production of
aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (See
PRECAUTIONS, Drug Interactions, Agents Increasing Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment, except
under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be
required in the treatment of metabolic alkalosis.
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Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water
restriction, rather than administration of salt except in rare instances when the hyponatremia is life-
threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest
during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation
of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may
be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment with
angiotensin-converting enzyme inhibitors, including ZESTORETIC. Patients should be so advised and
told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities,
eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have
consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the
first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall
in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as
vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with
their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which may be a sign of leukopenia/neutropenia.
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Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to
ZESTORETIC during pregnancy. Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with ZESTORETIC is
warranted. This information is intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Drug Interactions
Lisinopril
Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril
can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a
dose of 5 mg daily, and provide close medical supervision after the initial dose for at least two hours and
until blood pressure has stabilized for at least an additional hour (See WARNINGS, and DOSAGE AND
ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril, an
additional antihypertensive effect is usually observed (See DOSAGE AND ADMINISTRATION).
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute
renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving lisinopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is
associated with increased risks of hypotension, hyperkalemia, and changes in renal function
(including acute renal failure) compared to monotherapy.
The VA NEPHRON trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-
to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 ml/min),
randomized them to lisinopril or placebo on a background of losartan therapy and followed them
for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not
obtain any additional benefit compared to monotherapy for the combined endpoint of decline in
GFR, end state renal disease, or death, but experienced an increased incidence of hyperkalemia
and acute kidney injury compared with the monotherapy group.
In general, avoid combined use of RAS inhibitors, closely monitor blood pressure, renal function
and electrolytes in patients on ZESTORETIC and other agents that affect the RAS.
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Do not co-administer aliskiren with ZESTORETIC in patients with diabetes. Avoid use of
aliskiren with ZESTORETIC in patients with renal impairment (GFR < 60 ml/min).
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. No meaningful clinically important pharmacokinetic
interactions occurred when lisinopril was used concomitantly with propranolol, digoxin, or
hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type
diuretics. Use of lisinopril with potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene,
or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant
increases in serum potassium. Therefore, if concomitant use of these agents is indicated, because of
demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum
potassium.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs
which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible
upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be
monitored frequently if lisinopril is administered concomitantly with lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be
required.
Other antihypertensive drugs - additive effect or potentiation.
Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the
hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (eg, norepinephrine) - possible decreased response to pressor amines but not sufficient
to preclude their use.
Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine) - possible increased responsiveness to
the muscle relaxant.
Lithium - should not generally be given with diuretics. Diuretic agents reduce the renal clearance of
lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before
use of such preparations with ZESTORETIC.
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Non-Steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-
inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-
sparing and thiazide diuretics. Therefore, when ZESTORETIC and non-steroidal anti-inflammatory
agents are used concomitantly, the patient should be observed closely to determine if the desired effect of
ZESTORETIC is obtained.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have
been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant
ACE inhibitor therapy including ZESTORETIC.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril and Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using
Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a
forward mutation assay using Chinese hamster lung cells. Lisinopril and hydrochlorothiazide did not
produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, it did
not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in
an in vivo study in mouse bone marrow.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male
and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily human dose, based
on body weight and body surface area, respectively). There was no evidence of carcinogenicity when
lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about
84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human
dose based on body surface area in mice.
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2 .
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It
was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition,
lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster
ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to 300
mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily human dose based on
mg/kg and mg/m2, respectively.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology
Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice
(at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to
approximately 100 mg/kg/day). These doses are 150 times and 12 times for mice and 25 times and 4
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times for rats the maximum human daily dose based on mg/kg and mg/m2, respectively. The NTP,
however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary
(CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes,
Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.
Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity)
and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
from 43 to 1300 μg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified
concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies
wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior
to conception and throughout gestation. In mice this dose is 25 times and 2 times the maximum daily
human dose based on mg/kg and mg/m2, respectively. In rats this dose is 1 times and 0.2 times the
maximum daily human dose based on mg/kg and mg/m2, respectively.
Nursing Mothers
It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains
radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk
at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the
potential for serious adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a
decision should be made whether to discontinue nursing and/or discontinue ZESTORETIC, taking into
account the importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to ZESTORETIC:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or
substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from
neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed
by exchange transfusion, although there is no experience with the latter procedure.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of ZESTORETIC did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience has
not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
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This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function.
ADVERSE REACTIONS
ZESTORETIC has been evaluated for safety in 930 patients including 100 patients treated for 50 weeks
or more.
In clinical trials with ZESTORETIC no adverse experiences peculiar to this combination drug have been
observed. Adverse experiences that have occurred have been limited to those that have been previously
reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with
any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5%), headache (5.2%), cough
(3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were more common than in placebo-
treated patients. Generally, adverse experiences were mild and transient in nature, but see WARNINGS
regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse
effects was required in 4.4% of patients principally because of dizziness, cough, fatigue and muscle
cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies
Lisinopril and Hydrochlorothiazide (n=930)
Placebo (n=207)
Incidence (discontinuation)
Incidence
Dizziness
7.5
(0.8)
1.9
Headache
5.2
(0.3)
1.9
Cough
3.9
(0.6)
1.0
Fatigue
3.7
(0.4)
1.0
Orthostatic Effects
3.2
(0.1)
1.0
Diarrhea
2.5
(0.2)
2.4
Nausea
2.2
(0.1)
2.4
Upper Respiratory
2.2
(0.0)
0.0
Infection
Muscle Cramps
2.0
(0.4)
0.5
Asthenia
1.8
(0.2)
1.0
Paresthesia
1.5
(0.1)
0.0
Hypotension
1.4
(0.3)
0.5
Vomiting
1.4
(0.1)
0.5
Dyspepsia
1.3
(0.0)
0.0
Rash
1.2
(0.1)
0.5
Impotence
1.2
(0.3)
0.0
Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer, serious,
possibly drug-related events reported in marketing experience are listed below:
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Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.
Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth,
constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia,
foot pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory:
Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion,
chronic sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation,
diaphoresis, cutaneous pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital:
Urinary tract infection.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported
(See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension
(1.4%), orthostatic hypotension (0.5%), other orthostatic effects (3.2%). In addition syncope occurred in
0.8% of patients (See WARNINGS).
Cough: See PRECAUTIONS - Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: (See PRECAUTIONS).
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum
creatinine were observed in patients with essential hypertension treated with ZESTORETIC. More
marked increases have also been reported and were more likely to occur in patients with renal artery
stenosis (See PRECAUTIONS).
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See
PRECAUTIONS).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive patients treated
with ZESTORETIC but were rarely of clinical importance unless another cause of anemia coexisted. In
clinical trials, 0.4% of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See
WARNINGS, Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with
ZESTORETIC. In addition, and since lisinopril has been marketed, the following adverse reactions have
been reported with lisinopril and should be considered potential adverse reactions for ZESTORETIC:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;
Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary
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to excessive hypotension in high risk patients (see WARNINGS, Hypotension), pulmonary embolism and
infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris,
transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema,
vasculitis; Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus,
inappropriate antidiuretic hormone secretion; Hematologic: Rare cases of bone marrow depression,
hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported in which a causal
relationship to lisinopril can not be excluded; Metabolic: Gout, weight loss, dehydration, fluid overload,
weight gain; Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain,
lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (eg, paresthesia, dysesthesia), spasm, hypersomnia,
irritability; mood alterations (including depressive symptoms); hallucinations; Respiratory: Malignant
lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural
effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful respiration, epistaxis,
laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities; Skin: Urticaria, alopecia,
herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, psoriasis, rare cases
of other severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome
(causal relationship has not been established); Special Senses: Visual loss, diplopia, photophobia, taste
alteration, olfactory disturbance; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive
azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),
pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated
erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Hydrochlorothiazide - Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping,
jaundice (intrahepatic cholestatic jaundice) (See WARNINGS, Hepatic Failure), pancreatitis,
sialoadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic
anemia, hemolytic anemia; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric:
Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin:
Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic
epidermal necrolysis, alopecia; Special Senses: Xanthopsia; Hypersensitivity: Purpura,
photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress
including pneumonitis and pulmonary edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with ZESTORETIC. Treatment is
symptomatic and supportive. Therapy with ZESTORETIC should be discontinued and the patient
observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction
of dehydration, electrolyte imbalance and hypotension by established procedures.
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Lisinopril
Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of 20 mice
receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which
the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During
Membrane Exposure).
Hydrochlorothiazide
Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most common
signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia,
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide monotherapy is effective in doses of 12.5 - 50 mg per day. In clinical trials of
lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and
hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with
increasing dose of either component.
The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose;
those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and
dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy
with any combination of lisinopril and hydrochlorothiazide may be associated with either or both dose-
independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the
hypokalemia normally seen with diuretics.
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy only after
a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled
with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril/HCTZ 10/12.5 or
lisinopril/HCTZ 20/12.5, depending on current monotherapy dose. Further increases of either or both
components should depend on clinical response with blood pressure measured at the interdosing interval
to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose
should generally not be increased until 2-3 weeks have elapsed. After addition of the diuretic it may be
possible to reduce the dose of lisinopril. Patients whose blood pressures are adequately controlled with
25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen may
achieve similar or greater blood-pressure control without electrolyte disturbance if they are switched to
lisinopril/HCTZ 10/12.5.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may
occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to
three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (See
Reference ID: 3678299
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS). If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may
be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour
(See WARNINGS and PRECAUTIONS, Drug Interactions).
Concomitant administration of ZESTORETIC with potassium supplements, potassium salt substitutes or
potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).
Replacement Therapy: The combination may be substituted for the titrated individual components.
Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of renal
function as long as the patient's creatinine clearance is >30 mL/min/1.7m2 (serum creatinine roughly ≤3
mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to
thiazides, so lisinopril/HCTZ is not recommended (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure).
HOW SUPPLIED
ZESTORETIC 10-12.5 Tablets (NDC 0310-0141) Peach, round, biconvex, uncoated tablets identified
with "141" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
ZESTORETIC 20-12.5 Tablets (NDC 0310-0142) White, round, biconvex, uncoated tablets identified
with "142" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
ZESTORETIC 20-25 Tablets (NDC 0310-0145) Peach, round, biconvex, uncoated tablets identified
with “145” debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 100
tablets.
Storage
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from excessive light and
humidity.
*AN69 is a registered trademark of Hospal Ltd.
ZESTORETIC is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2012
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Revision: December 2014
Reference ID: 3678299
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:14.489010
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019888s056lbl.pdf', 'application_number': 19888, 'submission_type': 'SUPPL ', 'submission_number': 56}
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11,820
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Rx only
DILAUDID® ORAL LIQUID
CII
and DILAUDID® 8 mg TABLETS
(hydromorphone hydrochloride)
WARNING: DILAUDID ORAL LIQUID AND DILAUDID 8 MG TABLETS CONTAIN
HYDROMORPHONE, WHICH IS A POTENT SCHEDULE II CONTROLLED OPIOID
AGONIST. SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE,
OXYMORPHONE, OXYCODONE, FENTANYL, AND METHADONE, HAVE THE
HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING RESPIRATORY
DEPRESSION. ALCOHOL, OTHER OPIOIDS AND CENTRAL NERVOUS SYSTEM
DEPRESSANTS (SEDATIVE-HYPNOTICS) POTENTIATE THE RESPIRATORY
DEPRESSANT EFFECTS OF HYDROMORPHONE, INCREASING THE RISK OF
RESPIRATORY DEPRESSION THAT MIGHT RESULT IN DEATH.
DESCRIPTION:
DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid
analgesic.
The chemical name of DILAUDID (hydromorphone hydrochloride) is 4,5α-epoxy-3-hydroxy-
17-methylmorphinan-6-one hydrochloride. The structural formula is:
M.W. 321.8
Each 5 mL (1 teaspoon) of DILAUDID ORAL LIQUID contains 5 mg of hydromorphone
hydrochloride. In addition, other ingredients include purified water, methylparaben, propylparaben,
sucrose, and glycerin. DILAUDID ORAL LIQUID may contain traces of sodium metabisulfite.
Each DILAUDID 8 mg TABLET contains 8 mg hydromorphone hydrochloride. In addition,
the tablets include lactose anhydrous, and magnesium stearate. DILAUDID 8 mg TABLET may
contain traces of sodium metabisulfite.
CLINICAL PHARMACOLOGY:
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity
of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness.
Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes,
mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. Many
of the effects described below are common to this class of mu-opioid agonist analgesics which
includes morphine, oxycodone, hydrocodone, codeine and fentanyl. In some instances, data may not
exist to distinguish the effects of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS from
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 2
those observed with other opioid analgesics. However, in the absence of data to the contrary, it is
assumed that DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS would possess all the
actions of mu-agonist opioids.
Central Nervous System:
The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate
receptors have been identified. Opioids are believed to express their pharmacological effects by
combining with these receptors.
Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.
Hydromorphone depresses the respiratory reflex by a direct effect on brain stem respiratory centers.
The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain
stem respiratory centers to increases in carbon dioxide tension.
Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not
pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
Marked mydriasis rather than miosis may be seen with hypoxia in the setting of DILAUDID overdose,.
Gastrointestinal Tract and Other Smooth Muscle: Gastric, biliary and pancreatic secretions are
decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility
associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small
intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon
are decreased, and tone may be increased to the point of spasm. The end result is constipation.
Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the
sphincter of Oddi.
Cardiovascular System: Hydromorphone may produce hypotension as a result of either peripheral
vasodilation or release of histamine, or both. Other manifestations of histamine release and/or
peripheral vasodilation may include pruritus, flushing, and red eyes.
PHARMACOKINETICS AND METABOLISM:
The analgesic activity of DILAUDID (hydromorphone hydrochloride) is due to the parent drug,
hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract after oral
administration and undergoes extensive first-pass metabolism. Exposure of hydromorphone (Cmax and
AUC0-24) is dose-proportional at a dose range of 2 and 8 mg. In vivo bioavailability following single-
dose administration of the 8 mg tablet is approximately 24% (coefficient of variation 21%).
Bioequivalence between the DILAUDID 8 mg TABLET and an equivalent dose of DILAUDID ORAL
LIQUID has been demonstrated.
Absorption: After oral administration of DILAUDID 8 mg liquid or tablets, peak plasma
hydromorphone concentrations are generally attained within ½ to 1-hour.
Mean (%cv)
Cmax
Tmax
AUC
T½
Dosage Form
(ng)
(hrs)
(ng*hr/mL)
(hrs)
8 mg Tablet
5.5
(33%)
0.74 (34%)
23.7 (28%)
2.6
(18%)
8 mg Oral Liquid
5.7
(31%)
0.73 (71%)
24.6 (29%)
2.8
(20%)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 3
Food effects: In a study conducted with a single 8 mg dose of hydromorphone (2 mg DILAUDID® IR
tablets), food lowered Cmax by 25%, prolonged Tmax by 0.8 hour, and increased AUC by 35%. The
effects may not be clinically relevant.
Distribution: At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma
proteins. After an intravenous bolus dose, the steady state of volume distribution [mean (%cv)] is
302.9 (32%) liters.
Metabolism: Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater
than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-
hydroxy reduction metabolites.
Elimination: Only a small amount of the hydromorphone dose is excreted unchanged in the urine.
Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy
reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The
terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.
Special Populations:
Hepatic Impairment: After oral administration of hydromorphone at a single 4 mg dose (2 mg
Dilaudid IR Tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4-fold in
patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal
hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic
impairment should be started at a lower dose and closely monitored during dose titration.
Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied.
Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose
should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE
and ADMINISTRATION.
Renal Impairment: After oral administration of hydromorphone at a single 4 mg dose ( 2 mg Dilaudid
IR Tablets), exposure to hydromorphone ( Cmax and AUC0-48) is increased in patients with impaired
renal function by 2-fold in moderate (CLcr = 40 - 60 mL/min) and 3-fold in severe (CLcr < 30
mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in
patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with
longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr).
Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients
with severe renal impairment should be even lower. Patients with renal impairment should be closely
monitored during dose titration. Use of oral liquid is recommended to adjust the dose (see DOSAGE
and ADMINISTRATION).
.
Pediatrics: Pharmacokinetics of hydromorphone have not been evaluated in children.
Geriatric: Age has no effect on the pharmacokinetics of hydromorphone.
Gender: Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have
higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may
not be clinically relevant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 4
Pregnancy and nursing mothers: Hydromorphone crosses the placenta. Hydromorphone is also
found in low levels in breast milk, and may cause respiratory compromise in newborns when
administered during labor or delivery.
CLINICAL TRIALS:
Analgesic effects of single doses of DILAUDID ORAL LIQUID administered to patients with
post-surgical pain have been studied in double-blind controlled trials. In one study , both 5 mg and 10
mg of DILAUDID ORAL LIQUID provided significantly more analgesia than placebo. In another
trial, 5 mg and 10 mg of DILAUDID ORAL LIQUID were compared to 30 mg and 60 mg of morphine
sulfate oral liquid. The pain relief provided by 5 mg and 10 mg DILAUDID ORAL LIQUID was
comparable to 30 mg and 60 mg oral morphine sulfate, respectively.
INDICATIONS AND USAGE:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are indicated for the
management of pain in patients where an opioid analgesic is appropriate.
CONTRAINDICATIONS:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are contraindicated in: patients
with known hypersensitivity to hydromorphone, patients with respiratory depression in the absence of
resuscitative equipment, and in patients with status asthmaticus. DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS are also contraindicated for use in obstetrical analgesia.
WARNINGS:
Respiratory Depression: Respiratory depression is the chief hazard of DILAUDID ORAL LIQUID
and DILAUDID 8 mg TABLETS. Respiratory depression is more likely to occur in the elderly, in the
debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even
moderate therapeutic doses may dangerously decrease pulmonary ventilation.
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be used with extreme caution in
patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially
decreased respiratory reserve, hypoxia, hypercapnia, or in patients with preexisting respiratory
depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory
drive while simultaneously increasing airway resistance to the point of apnea.
DILAUDID ORAL LIQUID and DILAUDID 8mg TABLETS contain hydromorphone, which is
a potent Schedule II controlled opioid agonist. Schedule II opioid agonists, including morphine,
oxymorphone, oxycodone, fentanyl, and methadone, have the highest potential for abuse and
risk of producing respiratory depression. Alcohol, other opioids and central nervous system
depressants (sedative-hypnotics) potentiate the respiratory depressant effects of
hydromorphone, increasing the risk of respiratory depression that might result in death.
Misuse, Abuse, and Diversion of Opioids:
Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and
people with addiction disorders and are subject to criminal diversion.
DILAUDID can be abused in a manner similar to other opioid agonists, legal or illicit. This should be
considered when prescribing or dispensing DILAUDID in situations where the physician or
pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 5
monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients
should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy.
Persons at increased risk for opioid abuse include those with a personal or family history of substance
abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be
appropriate for use in these patients, however, they will require intensive monitoring for signs of
abuse.
DILAUDID has been reported as being abused by crushing, chewing, snorting, or injecting the
dissolved product. These practices pose a significant risk to the abuser that could result in overdose or
death (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled
Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse:
Hydromorphone may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression.
Neonatal Withdrawal Syndrome: Infants born to mothers physically dependent on DILAUDID will
also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see
DRUG ABUSE AND DEPENDENCE).
Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of DILAUDID
ORAL LIQUID and DILAUDID 8 mg TABLETS with carbon dioxide retention and secondary
elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury,
other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including
DILAUDID® ORAL LIQUID and DILAUDID 8 mg TABLETS (hydromorphone hydrochloride) may
produce effects on pupillary response and consciousness which can obscure the clinical course and
neurologic signs of further increase in intracranial pressure in patients with head injuries.
Hypotensive Effect: Opioid analgesics, including DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS, may cause severe hypotension in an individual whose ability to maintain blood pressure
has already been compromised by a depleted blood volume, or a concurrent administration of drugs
such as phenothiazines or general anesthetics (see PRECAUTIONS Drug Interactions). Therefore,
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be administered with caution to
patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac
output and blood pressure.
Sulfites: Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible
people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably
low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 6
PRECAUTIONS:
Special Risk Patients: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be
given with caution and the initial dose should be reduced in the elderly or debilitated and those with
severe impairment of hepatic, pulmonary or renal functions; myxedema or hypothyroidism;
adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses;
prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens;
kyphoscoliosis or following gastrointestinal surgery.
The administration of opioid analgesics including DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS may obscure the diagnoses or clinical course in patients with acute
abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders.
Reports of mild to severe seizures and myoclonus have been reported in severely compromised
patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid
administration at very high doses is associated with seizures and myoclonus in a variety of diseases
where pain control is the primary focus.
Use in Drug and Alcohol Dependent Patients : DILAUDID should be used with caution in patients
with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance,
dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID in
combination with other CNS depressant drugs can result in serious risk to the patient.
Hydromorphone is an opioid with no approved use in the management of addictive disorders.
Use in Ambulatory Patients: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS may
impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g.
driving, operating machinery). Patients should be cautioned accordingly. DILAUDID may produce
orthostatic hypotension in ambulatory patients.
Use in Biliary Tract Disease: Opioid analgesics, including DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS, should also be used with caution in patients about to undergo surgery of
the biliary tract since it may cause spasm of the sphincter of Oddi.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in
the absence of disease progression or other external factors). Physical dependence is manifested by
withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.
Physical dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other
symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
In general, opioids used regularly should not be abruptly discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 7
Information for Patients/Caregivers
Patients receiving DILAUDID (hydromorphone hydrochloride) ORAL LIQUID or DILAUDID 8 mg
TABLETS or their caregivers should be given the following information by the physician, nurse, or
pharmacist:
1. Patients should be aware that DILAUDID tablets contain hydromorphone, which is a morphine-
like substance and which could cause severe adverse effects including respiratory depression and
even death if not taken according to the prescriber’s directions.
2. Patients should be advised to report pain and adverse experiences occurring during therapy.
Individualization of dosage is essential to make optimal use of this medication.
3. Patients should be advised not to adjust the dose of DILAUDID without consulting the prescribing
professional.
4. Patients should be advised that DILAUDID may impair mental and/or physical ability required for
the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
5. Patients should not combine DILAUDID with alcohol or other central nervous system depressants
(sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous
additive effects may occur, resulting in serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant should be
advised to consult their physician regarding the effects of analgesics and other drug use during
pregnancy on themselves and their unborn child.
7. Patients should be advised that DILAUDID is a potential drug of abuse. They should protect it
from theft, and it should never be given to anyone other than the individual for whom it was
prescribed.
8. Patients should be advised that if they have been receiving treatment with DILAUDID for more
than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the
DILAUDID dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal
symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of
the medication.
9. Patients should be instructed to keep DILAUDID in a secure place out of the reach of children.
When DILAUDID is no longer needed, the unused tablets should be destroyed by flushing down
the toilet.
Drug Interactions
Drug Interactions with Other CNS Depressants: The concomitant use of other central nervous
system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers
and alcohol may produce additive depressant effects. Respiratory depression, hypotension and
profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one
or both agents should be reduced. DILAUDID should not be taken with alcohol. Opioid analgesics,
including DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS, may enhance the action of
neuromuscular blocking agents and produce an excessive degree of respiratory depression.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 8
Interactions with Mixed Agonist/Antagonist Opioid
Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should
be administered with caution to a patient who has received or is receiving a course of therapy with a
pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist
analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal
symptoms in these patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No carcinogenicity studies have been conducted in animals.
Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay or the human
lymphocyte chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse
micronucleus assay.
No effects on fertility, reproductive performance, or reproductive organ morphology were
observed y in male or female rats given oral doses up to 7 mg/kg/day, which is equivalent to the
human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of
2-4 mg every 4 to 6 hours for the tablet on a body surface area basis..
PREGNANCY-PREGNANCY CATEGORY C: No effects on teratogenicity or embryotoxicity were
observed in female rats given oral doses up to 7 mg/kg/day, which is approximately equivalent to the
human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of
2-4 mg every 4 to 6 hours for the tablet on a body surface area basis. Hydromorphone produced skull
malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg
during the peak of organogenesis (gestation days 8-9). The skull malformations were observed at
doses approximately 2-fold higher the human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and
7-fold higher than the human dose of 2-4 mg every 4 to 6 hours for the tablet on a body surface area
basis. There are no adequate and well-controlled studies of DILAUDID in pregnant women.
Hydromorphone crosses the placenta, resulting in fetal exposure. DILAUDID ORAL LIQUID
and DILAUDID 8 mg TABLETS should be used in pregnant women only if the potential benefit
justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND
DEPENDENCE).
Nonteratogenic effects: Babies born to mothers who have been taking opioids regularly prior to
delivery will be physically dependent. The withdrawal signs include irritability and excessive crying,
tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning,
vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of
maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.
Approaches to the treatment of this syndrome have included supportive care and, when indicated,
drugs such as paregoric or phenobarbital.
Labor and Delivery: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are
contraindicated in Labor and Delivery (see CONTRAINDICATIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 9
Nursing Mothers: Low levels of opioid analgesics have been detected in human milk. As a general
rule, nursing should not be undertaken while a patient is receiving DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS since it, and other drugs in this class, may be excreted in the milk.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: Clinical studies of DILAUDID did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy (see INDIVIDUALIZATION OF DOSAGES and PRECAUTIONS).
ADVERSE REACTIONS:
The major hazards of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS include
respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock
and cardiac arrest have occurred.
The most frequently observed adverse effects are light-headedness, dizziness, sedation, nausea,
vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be
more prominent in ambulatory patients and in those not experiencing severe pain.
Less Frequently Observed Adverse Reactions:
General and CNS: Weakness, headache, agitation, tremor, uncoordinated muscle movements,
alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity,
paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and
disorientation, visual disturbances, insomnia, increased intracranial pressure
Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope,
hypotension, hypertension.
Respiratory: Bronchospasm and laryngospasm
Gastrointestinal: Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps, taste alteration
Genitourinary: Urinary retention or hesitancy, antidiuretic effects
Dermatologic: Urticaria, other skin rashes, diaphoresis.
OVERDOSAGE:
Serious overdosage with DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS is
characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle
flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In
serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac
arrest and death may occur.
In the treatment of overdosage, primary attention should be given to the reestablishment of
adequate respiratory exchange through provision of a patent airway and institution of assisted or
controlled ventilation. A potentially serious oral ingestion, if recent, should be managed with gut
decontamination. In unconscious patients with a secure airway, instill activated charcoal (30-100 g in
adults, 1-2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the
first dose of activated charcoal.
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NDA 19-891/S-008
NDA 19-892/S-009
Page 10
Supportive measures (including oxygen, vasopressors) should be employed in the management
of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or
arrhythmias may require cardiac massage or defibrillation.
The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result
from overdosage, or unusual sensitivity to DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS. Therefore, an appropriate dose of this antagonist should be administered, preferably by the
intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be
administered in the absence of clinically significant respiratory or circulatory depression. Naloxone
should be administered cautiously to persons who are known, or suspected to be physically dependent
on DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS . In such cases, an abrupt or
complete reversal of narcotic effects may precipitate an acute withdrawal syndrome. Since the duration
of action of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS may exceed that of the
antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist
may be required to maintain adequate respiration. Apply other supportive measures when indicated.
DOSAGE AND ADMINISTRATION:
DILAUDID ORAL LIQUID: The usual adult oral dosage of DILAUDID ORAL LIQUID is one-half
(2.5 mL) to two teaspoonfuls (10 mL) (2.5 mg - 10 mg) every 3 to 6 hours as directed by the clinical
situation. Oral dosages higher than the usual dosages may be required in some patients.
DILAUDID 8 mg TABLET: The usual starting dose for DILAUDID tablets is 2 mg to 4 mg, orally,
every 4 to 6 hours. Appropriate use of the DILAUDID 8 mg TABLET must be decided by careful
evaluation of each clinical situation.
A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or
if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.
Patients with hepatic and renal impairment should be started on a lower starting dose (See
CLINCIAL PHARMCOLOGY :PHARMACOKINETICS and METABOLISM).
INDIVIDUALIZATION OF DOSAGE:
The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized
for any given patient, since adverse events can occur at doses that may not provide complete freedom
from pain.
Safe and effective administration of opioid analgesics to patients with acute or chronic pain
depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency,
etiology, and pathophysiology) as well as the concurrent medical status of the patient will affect
selection of the starting dosage.
In non-opioid-tolerant patients, therapy with hydromorphone is typically initiated at an oral
dose of 2-4 mg every four hours, but elderly patients may require lower doses (see PRECAUTIONS -
Geriatric Use).
In patients receiving opioids, both the dose and duration of analgesia will vary substantially
depending on the patient's opioid tolerance. The dose should be selected and adjusted so that at least 3-
4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of
DILAUDID should be based on prior opioid usage. This should be done by converting the total daily
usage of the previous opioid to an equivalent total daily dosage of oral DILAUDID using an
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NDA 19-891/S-008
NDA 19-892/S-009
Page 11
equianalgesic table (see below). For opioids not in the table, first estimate the equivalent total daily
usage of oral morphine, then use the table to find the equivalent total daily dosage of DILAUDID.
Once the total daily dosage of DILAUDID has been estimated, it should be divided into the
desired number of doses. Since there is individual variation in response to different opioid drugs, only
1/2 to 2/3 of the estimated dose of DILAUDID calculated from equivalence tables should be given for
the first few doses, then increased as needed according to the patient's response.
Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment
with a consequent increase in exposure, Patients with hepatic and renal impairment should be started
on a lower starting dose (See CLINCIAL PHARMCOLOGY :PHARMCOKINETICS and
METABOLISM).
In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5-15%
of the total daily usage may be administered every two hours on an "as-needed" basis.
Periodic reassessment after the initial dosing is always required. If pain management is not
satisfactory and in the absence of significant opioid-induced adverse events, the hydromorphone dose
may be increased gradually. If excessive opioid side effects are observed early in the dosing interval,
the hydromorphone dose should be reduced. If this results in breakthrough pain at the end of the dosing
interval, the dosing interval may need to be shortened. Dose titration should be guided more by the
need for analgesia than the absolute dose of opioid employed.
OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC POTENCY*
Nonproprietary
(Trade) Name
IM or SC
Dose
ORAL
Dose
Morphine sulfate
10mg
40-60mg
Hydromorphone HCl
(DILAUDID)
1.3-2mg
6.5-7.5mg
Oxymorphone HCl
(Numorphan)
1-1.1mg
6.6mg
Levorphanol tartrate
(Levo-Dromoran)
2-2.3mg
4mg
Meperidine, pethidine HCl
(Demerol)
75-100mg
300-400mg
Methadone HCl
(Dolophine)
10mg
10-20mg
* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references
comparing opioid analgesics in cancer and severe pain.
DRUG ABUSE AND DEPENDENCE
DILAUDID ORAL LIQUID and DILAUDID 8 MG TABLETS contain hydromorphone, a
Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine,
oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk
of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion.
Opioid analgesics may cause psychological and physical dependence. Physical dependence
results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical
dependence usually does not occur to a clinically significant degree until after several weeks of
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NDA 19-891/S-008
NDA 19-892/S-009
Page 12
continued opioid usage, but it may occur after as little as a week of opioid use. Physical
dependence and tolerance are separate and distinct from abuse and addiction.
Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors
influencing its development and manifestations. It is characterized by behaviors that include one or
more of the following: impaired control over drug use, compulsive use, continued use despite harm,
and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is
common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include
emergency calls or visits near the end of office hours, refusal to undergo appropriate examination,
testing or referral, repeated “loss” of prescriptions, tampering with, forging or counterfeiting
prescriptions and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers,
people suffering from untreated addiction and criminals seeking drugs to sell.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of addiction and is characterized by misuse for non-medical purposes, often in combination
with other psychoactive substances. Since DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS may be diverted for non-medical use, careful record keeping of prescribing information,
including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and
proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are intended for oral use only. Misuse
or abuse of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS pose a risk of overdose and
death. This risk is increased with concurrent abuse of alcohol and other CNS depressants. Parenteral
drug abuse can potentially result in local tissue necrosis, infection, pulmonary granulomas, and
increased risk of endocarditis and valvular heart injury. In addition, parenteral abuse is commonly
associated with transmission of infectious diseases such as hepatitis and HIV.
SAFETY AND HANDLING INSTRUCTIONS:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS pose little risk of direct
exposure to health care personnel and should be handled and disposed of prudently in accordance with
hospital or institutional policy. Significant absorption from dermal exposure is unlikely; accidental
dermal exposure to DILAUDID ORAL LIQUID should be treated by removal of any contaminated
clothing and rinsing the affected area with cool water. Patients and their families should be instructed
to flush any DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS that are no longer needed.
Access to abuseable drugs such as DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS presents an occupational hazard for addiction in the health care industry. Routine
procedures for handling controlled substances developed to protect the public may not be adequate to
protect health care workers. Implementation of more effective accounting procedures and measures to
restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-
administration by health care providers.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 13
HOW SUPPLIED:
DILAUDID ORAL LIQUID is a clear, sweet, slightly viscous liquid. It is available in:
Bottles of 1 pint (473 mL)-NDC# 0074-2452-02
DILAUDID 8 mg TABLETS are white and triangular shaped, embossed with the number 8 on one
side and bisected and embossed with a double
on the other side. They are available in:
Bottles of 100-NDC# 0074-2426-14
STORAGE: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled
Room Temperature]. Protect from light.
A schedule CII Narcotic. DEA Order Form is Required.
©Abbott
All rights reserved.
Revised: NEW
NEW
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:14.589132
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019892s009,019891s008lbl.pdf', 'application_number': 19891, 'submission_type': 'SUPPL ', 'submission_number': 8}
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ZESTORETIC®
(lisinopril and hydrochlorothiazide)
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue ZESTORETIC as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. See Warnings: Fetal Toxicity.
DESCRIPTION
ZESTORETIC® (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme
inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor.
It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its
empirical formula is C21H31N3O5 . 2H2O and its structural formula is:
structural formula
water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is C7H8ClN3O4S2 and its structural formula is: structural formula
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of
297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
ZESTORETIC is available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide:
ZESTORETIC 10-12.5 containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide; ZESTORETIC 20
Reference ID: 3811027
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12.5 containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and, ZESTORETIC 20-25 containing
20 mg lisinopril and 25 mg hydrochlorothiazide.
Inactive Ingredients:
10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, starch.
20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch, yellow ferric
oxide.
CLINICAL PHARMACOLOGY
Lisinopril and Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases
aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the renin
angiotensin aldosterone axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and
hydrochlorothiazide was approximately additive. The ZESTORETIC 10-12.5 combination worked
equally well in black and white patients. The ZESTORETIC 20-12.5 and ZESTORETIC 20-25
combinations appeared somewhat less effective in black patients, but relatively few black patients were
studied. In most patients, the antihypertensive effect of ZESTORETIC was sustained for at least 24
hours.
In a randomized, controlled comparison, the mean antihypertensive effects of ZESTORETIC 20-12.5 and
ZESTORETIC 20-25 were similar, suggesting that many patients who respond adequately to the latter
combination may be controlled with ZESTORETIC 20-12.5 (See DOSAGE AND
ADMINISTRATION).
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the
bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of
the separate entities.
Lisinopril
Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of
ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to
decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the
mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of
Reference ID: 3811027
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patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than
0.5 mEq/L. In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially
no change in serum potassium (See PRECAUTIONS).
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be
elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients
with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, black
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
lisinopril monotherapy than nonblack patients.
Pharmacokinetics and Metabolism:
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours.
Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug
accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional
to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary
recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject
variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the
presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients (see
DOSAGE AND ADMINISTRATION). In a multiple dose pharmacokinetic study in elderly versus
young hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased
approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues; however, milk of lactating rats contains radioactivity
following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the
placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pharmacodynamics:
Administration of lisinopril to patients with hypertension results in a reduction of supine and standing
blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural
Reference ID: 3811027
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hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-
depleted patients (See WARNINGS).
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration
of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours,
after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after
dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of
lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot
of pretreatment blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in
controlling blood pressure (See PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect
normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of
electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in
approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and
bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have
been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8
hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide
crosses the placental but not the blood-brain barrier.
INDICATIONS AND USAGE
ZESTORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood
pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial
Reference ID: 3811027
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infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide
variety of pharmacologic classes including lisinopril and hydrochlorothiazide.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,
exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood
pressure goals. For specific advice on goals and management, see published guidelines, such as those of
the National High Blood Pressure Education Program’s Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other
pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most
consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in
myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase
per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can
provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across
populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk
independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such
patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and
many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart
failure, or diabetic kidney disease). These considerations may guide selection of therapy.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND
ADMINISTRATION).
In using ZESTORETIC, consideration should be given to the fact that an angiotensin-converting enzyme
inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen
vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk
(See WARNINGS).
In considering the use of ZESTORETIC, it should be noted that ACE inhibitors have been associated with
a higher rate of angioedema in black than in nonblack patients (see WARNINGS, Lisinopril).
CONTRAINDICATIONS
ZESTORETIC is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this
product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with ZESTORETIC in patients with diabetes (see PRECAUTIONS, Drug
Interactions).
Reference ID: 3811027
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WARNINGS
Lisinopril
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme
inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including ZESTORETIC) may be subject to a variety of adverse
reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This
may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in black than in nonblack patients. ZESTORETIC should be promptly discontinued and the
appropriate therapy and monitoring should be provided until complete and sustained resolution of signs
and symptoms has occurred. Even in those instances where swelling of only the tongue is involved,
without respiratory distress, patients may require prolonged observation since treatment with
antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to
angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue,
glottis or larynx are likely to experience airway obstruction, especially those with a history of airway
surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway
obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures
necessary to ensure a patent airway should be promptly provided (See ADVERSE REACTIONS).
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin)
inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see
PRECAUTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there
was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was
diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms
resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with
hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.
In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but
they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions during Membrane Exposure: Thiazide-containing combination products are
not recommended in patients with severe renal dysfunction. Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (eg,
AN69®*) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not
Reference ID: 3811027
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For current labeling information, please visit https://www.fda.gov/drugsatfda
been relieved by antihistamines in these situations. In these patients, consideration should be given to
using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid
reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive
patients but is a possible consequence of lisinopril use in salt/volume-depleted persons such as those
treated vigorously with diuretics or patients on dialysis (See PRECAUTIONS, Drug Interactions and
ADVERSE REACTIONS).
Syncope has been reported in 0.8 percent of patients receiving ZESTORETIC. In patients with
hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence
of syncope may be reduced by proper titration of the individual components (See PRECAUTIONS, Drug
Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive
hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and
rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these
patients, therapy should be started under very close medical supervision. Such patients should be
followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is
increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in
whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular
accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an
intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to
further doses which usually can be given without difficulty once the blood pressure has increased after
volume expansion.
Leukopenia/Neutropenia/Agranulocytosis: Another angiotensin-converting enzyme inhibitor, captopril,
has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients
but more frequently in patients with renal impairment, especially if they also have a collagen vascular
disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not
cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be
excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and
renal disease should be considered.
Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The
mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice
or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate
medical follow-up.
Fetal Toxicity
Pregnancy category D
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Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential
neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When
pregnancy is detected, discontinue ZESTORETIC as soon as possible. These adverse outcomes are
usually associated with use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first
trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive
agents. Appropriate management of maternal hypertension during pregnancy is important to optimize
outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin
angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform
serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,
discontinue ZESTORETIC, unless it is considered lifesaving for the mother. Fetal testing may be
appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe
infants with histories of in utero exposure to ZESTORETIC for hypotension, oliguria, and hyperkalemia.
(See Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg
basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the
maximum recommended human dose.
Lisinopril and Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril (56 times the
maximum recommended human dose) in combination with 10 mg/kg/day of hydrochlorothiazide (2.5
times the maximum recommended human dose). Maternal or fetotoxic effects were not seen in mice with
the combination. In rats decreased maternal weight gain and decreased fetal weight occurred down to
3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was a delay in fetal
ossification. The decreased fetal weight and delay in fetal ossification were not seen in saline-
supplemented animals given 90/10 mg/kg/day.
When used in pregnancy, during the second and third trimesters, ACE inhibitors can cause injury and
even death to the developing fetus. When pregnancy is detected, discontinue ZESTORETIC as soon as
possible (See Lisinopril, Fetal Toxicity).
Hydrochlorothiazide
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can
cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours
to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk
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factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin
allergy.
Teratogenic Effects: Reproduction studies in the rabbit, the mouse and the rat at doses up to 100
mg/kg/day (50 times the human dose) showed no evidence of external abnormalities of the fetus due to
hydrochlorothiazide. Hydrochlorothiazide given in a two-litter study in rats at doses of 4-5.6 mg/kg/day
(approximately 1-2 times the usual daily human dose) did not impair fertility or produce birth
abnormalities in the offspring. Thiazides cross the placental barrier and appear in cord blood.
Nonteratogenic Effects: These may include fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions have occurred in the adult.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides
may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal
function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (See PRECAUTIONS, Drug Interactions, Lisinopril
and Hydrochlorothiazide).
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given
with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe
congestive heart failure whose renal function may depend on the activity of the renin-angiotensin
aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including lisinopril, may be
associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen
and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor
suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic
therapy. In such patients renal function should be monitored during the first few weeks of therapy.
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Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases
in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function (See
DOSAGE AND ADMINISTRATION).
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In
most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a
cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium
supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes
fatal, arrhythmias. ZESTORETIC should be used cautiously, if at all, with these agents and with frequent
monitoring of serum potassium (See PRECAUTIONS, Drug Interactions).
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, almost always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce
hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If
hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume
expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed
at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or receiving
parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause,
include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after
prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may
cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic
effects of digitalis (eg, increased ventricular irritability). Because lisinopril reduces the production of
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aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (See
PRECAUTIONS, Drug Interactions, Agents Increasing Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment, except
under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be
required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water
restriction, rather than administration of salt except in rare instances when the hyponatremia is life-
threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest
during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation
of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may
be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment with
angiotensin-converting enzyme inhibitors, including ZESTORETIC. Patients should be so advised and
told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities,
eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have
consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the
first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall
in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as
vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with
their physician.
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Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to
ZESTORETIC during pregnancy. Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with ZESTORETIC is
warranted. This information is intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Drug Interactions
Lisinopril
Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril
can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a
dose of 5 mg daily, and provide close medical supervision after the initial dose for at least two hours and
until blood pressure has stabilized for at least an additional hour (See WARNINGS, and DOSAGE AND
ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril, an
additional antihypertensive effect is usually observed (See DOSAGE AND ADMINISTRATION).
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute
renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving lisinopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated
with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal
failure) compared to monotherapy.
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The VA NEPHRON trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to
creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 ml/min), randomized
them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2
years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit
compared to monotherapy for the combined endpoint of decline in GFR, end state renal disease, or death,
but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the
monotherapy group.
In general, avoid combined use of RAS inhibitors, closely monitor blood pressure, renal function and
electrolytes in patients on ZESTORETIC and other agents that affect the RAS.
Do not co-administer aliskiren with ZESTORETIC in patients with diabetes. Avoid use of aliskiren with
ZESTORETIC in patients with renal impairment (GFR < 60 ml/min).
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. No meaningful clinically important pharmacokinetic
interactions occurred when lisinopril was used concomitantly with propranolol, digoxin, or
hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type
diuretics. Use of lisinopril with potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene,
or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant
increases in serum potassium. Therefore, if concomitant use of these agents is indicated, because of
demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum
potassium.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs
which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible
upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be
monitored frequently if lisinopril is administered concomitantly with lithium.
mTOR (mammalian target of rapamycin) inhibitors
Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus,
everolimus) therapy may be at increased risk for angioedema (see WARNINGS)
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be
required.
Other antihypertensive drugs - additive effect or potentiation.
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Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the
hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (eg, norepinephrine) - possible decreased response to pressor amines but not sufficient
to preclude their use.
Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine) - possible increased responsiveness to
the muscle relaxant.
Lithium - should not generally be given with diuretics. Diuretic agents reduce the renal clearance of
lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before
use of such preparations with ZESTORETIC.
Non-Steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-
inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-
sparing and thiazide diuretics. Therefore, when ZESTORETIC and non-steroidal anti-inflammatory
agents are used concomitantly, the patient should be observed closely to determine if the desired effect of
ZESTORETIC is obtained.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have
been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant
ACE inhibitor therapy including ZESTORETIC.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril and Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using
Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a
forward mutation assay using Chinese hamster lung cells. Lisinopril and hydrochlorothiazide did not
produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, it did
not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in
an in vivo study in mouse bone marrow.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male
and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily human dose, based
on body weight and body surface area, respectively). There was no evidence of carcinogenicity when
lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about
84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human
dose based on body surface area in mice.
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2 .
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Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It
was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition,
lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster
ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to 300
mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily human dose based on
mg/kg and mg/m2, respectively.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology
Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice
(at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to
approximately 100 mg/kg/day). These doses are 150 times and 12 times for mice and 25 times and 4
times for rats the maximum human daily dose based on mg/kg and mg/m2, respectively. The NTP,
however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary
(CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes,
Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.
Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity)
and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
from 43 to 1300 μg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified
concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies
wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior
to conception and throughout gestation. In mice this dose is 25 times and 2 times the maximum daily
human dose based on mg/kg and mg/m2, respectively. In rats this dose is 1 times and 0.2 times the
maximum daily human dose based on mg/kg and mg/m2, respectively.
Nursing Mothers
It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains
radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk
at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the
potential for serious adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a
decision should be made whether to discontinue nursing and/or discontinue ZESTORETIC, taking into
account the importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to ZESTORETIC:
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If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or
substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from
neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed
by exchange transfusion, although there is no experience with the latter procedure.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of ZESTORETIC did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience has
not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function.
ADVERSE REACTIONS
ZESTORETIC has been evaluated for safety in 930 patients including 100 patients treated for 50 weeks
or more.
In clinical trials with ZESTORETIC no adverse experiences peculiar to this combination drug have been
observed. Adverse experiences that have occurred have been limited to those that have been previously
reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with
any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5%), headache (5.2%), cough
(3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were more common than in placebo-
treated patients. Generally, adverse experiences were mild and transient in nature, but see WARNINGS
regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse
effects was required in 4.4% of patients principally because of dizziness, cough, fatigue and muscle
cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies
Lisinopril and Hydrochlorothiazide (n=930)
Placebo (n=207)
Incidence (discontinuation)
Incidence
Dizziness
7.5
(0.8)
1.9
Headache
5.2
(0.3)
1.9
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Cough
3.9
(0.6)
1.0
Fatigue
3.7
(0.4)
1.0
Orthostatic Effects
3.2
(0.1)
1.0
Diarrhea
2.5
(0.2)
2.4
Nausea
2.2
(0.1)
2.4
Upper Respiratory
2.2
(0.0)
0.0
Infection
Muscle Cramps
2.0
(0.4)
0.5
Asthenia
1.8
(0.2)
1.0
Paresthesia
1.5
(0.1)
0.0
Hypotension
1.4
(0.3)
0.5
Vomiting
1.4
(0.1)
0.5
Dyspepsia
1.3
(0.0)
0.0
Rash
1.2
(0.1)
0.5
Impotence
1.2
(0.3)
0.0
Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer, serious,
possibly drug-related events reported in marketing experience are listed below:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.
Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth,
constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia,
foot pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory:
Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion,
chronic sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation,
diaphoresis, cutaneous pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital:
Urinary tract infection.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported
(See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension
(1.4%), orthostatic hypotension (0.5%), other orthostatic effects (3.2%). In addition syncope occurred in
0.8% of patients (See WARNINGS).
Cough: See PRECAUTIONS - Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: (See PRECAUTIONS).
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum
creatinine were observed in patients with essential hypertension treated with ZESTORETIC. More
marked increases have also been reported and were more likely to occur in patients with renal artery
stenosis (See PRECAUTIONS).
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Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See
PRECAUTIONS).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive patients treated
with ZESTORETIC but were rarely of clinical importance unless another cause of anemia coexisted. In
clinical trials, 0.4% of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See
WARNINGS, Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril - In clinical trials adverse reactions which occurred with lisinopril were also seen with
ZESTORETIC. In addition, and since lisinopril has been marketed, the following adverse reactions have
been reported with lisinopril and should be considered potential adverse reactions for ZESTORETIC:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;
Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high risk patients (see WARNINGS, Hypotension), pulmonary embolism and
infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris,
transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema,
vasculitis; Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus,
inappropriate antidiuretic hormone secretion; Hematologic: Rare cases of bone marrow depression,
hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported in which a causal
relationship to lisinopril can not be excluded; Metabolic: Gout, weight loss, dehydration, fluid overload,
weight gain; Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain,
lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (eg, paresthesia, dysesthesia), spasm, hypersomnia,
irritability; mood alterations (including depressive symptoms); hallucinations; Respiratory: Malignant
lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural
effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful respiration, epistaxis,
laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities; Skin: Urticaria, alopecia,
herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, psoriasis, rare cases
of other severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome
(causal relationship has not been established); Special Senses: Visual loss, diplopia, photophobia, taste
alteration, olfactory disturbance; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive
azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),
pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated
erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Reference ID: 3811027
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hydrochlorothiazide - Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping,
jaundice (intrahepatic cholestatic jaundice) (See WARNINGS, Hepatic Failure), pancreatitis,
sialoadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic
anemia, hemolytic anemia; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric:
Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin:
Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic
epidermal necrolysis, alopecia; Special Senses: Xanthopsia; Hypersensitivity: Purpura,
photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress
including pneumonitis and pulmonary edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with ZESTORETIC. Treatment is
symptomatic and supportive. Therapy with ZESTORETIC should be discontinued and the patient
observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction
of dehydration, electrolyte imbalance and hypotension by established procedures.
Lisinopril
Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of 20 mice
receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which
the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis (see WARNINGS, Anaphylactoid Reaction During
Membrane Exposure).
Hydrochlorothiazide
Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most common
signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia,
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide monotherapy is effective in doses of 12.5 - 50 mg per day. In clinical trials of
lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and
hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with
increasing dose of either component.
The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose;
those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and
dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy
with any combination of lisinopril and hydrochlorothiazide may be associated with either or both dose-
independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the
hypokalemia normally seen with diuretics.
Reference ID: 3811027
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy only after
a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled
with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril/HCTZ 10/12.5 or
lisinopril/HCTZ 20/12.5, depending on current monotherapy dose. Further increases of either or both
components should depend on clinical response with blood pressure measured at the interdosing interval
to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose
should generally not be increased until 2-3 weeks have elapsed. After addition of the diuretic it may be
possible to reduce the dose of lisinopril. Patients whose blood pressures are adequately controlled with
25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen may
achieve similar or greater blood-pressure control without electrolyte disturbance if they are switched to
lisinopril/HCTZ 10/12.5.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may
occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to
three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (See
WARNINGS). If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may
be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour
(See WARNINGS and PRECAUTIONS, Drug Interactions).
Concomitant administration of ZESTORETIC with potassium supplements, potassium salt substitutes or
potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).
Replacement Therapy: The combination may be substituted for the titrated individual components.
Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of renal
function as long as the patient's creatinine clearance is >30 mL/min/1.7m2 (serum creatinine roughly ≤3
mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to
thiazides, so lisinopril/HCTZ is not recommended (see WARNINGS, Anaphylactoid Reactions During
Membrane Exposure).
HOW SUPPLIED
ZESTORETIC 10-12.5 Tablets: Peach, round, biconvex, uncoated tablets identified with "141"
debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC
52427-435-90) and bottles of 100 tablets (NDC 52427-435-01).
ZESTORETIC 20-12.5 Tablets: White, round, biconvex, uncoated tablets identified with "142"
debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC
52427-436-90) and bottles of 100 tablets (NDC 52427-436-01).
Reference ID: 3811027
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZESTORETIC 20-25 Tablets: Peach, round, biconvex, uncoated tablets identified with “145” debossed
on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC 52427-437
90) and bottles of 100 tablets (NDC 52427-437-01).
Storage
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from excessive light and
humidity.
*AN69 is a registered trademark of Hospal Ltd.
ZESTORETIC is a trademark of Alvogen Pharma US, Inc.
Manufactured by:
AstraZeneca UK Limited,
Macclesfield, UK
Distributed by:
Almatica Pharma, Inc.
Pine Brook, NJ 07058 USA
PI435-04
Rev. 08/2015
Reference ID: 3811027
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:14.645002
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019888s065lbl.pdf', 'application_number': 19888, 'submission_type': 'SUPPL ', 'submission_number': 65}
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11,821
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Rx only
DILAUDID® ORAL LIQUID
CII
and DILAUDID® 8 mg TABLETS
(hydromorphone hydrochloride)
WARNING: DILAUDID ORAL LIQUID AND DILAUDID 8 MG TABLETS CONTAIN
HYDROMORPHONE, WHICH IS A POTENT SCHEDULE II CONTROLLED OPIOID
AGONIST. SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE,
OXYMORPHONE, OXYCODONE, FENTANYL, AND METHADONE, HAVE THE
HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING RESPIRATORY
DEPRESSION. ALCOHOL, OTHER OPIOIDS AND CENTRAL NERVOUS SYSTEM
DEPRESSANTS (SEDATIVE-HYPNOTICS) POTENTIATE THE RESPIRATORY
DEPRESSANT EFFECTS OF HYDROMORPHONE, INCREASING THE RISK OF
RESPIRATORY DEPRESSION THAT MIGHT RESULT IN DEATH.
DESCRIPTION:
DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid
analgesic.
The chemical name of DILAUDID (hydromorphone hydrochloride) is 4,5α-epoxy-3-hydroxy-
17-methylmorphinan-6-one hydrochloride. The structural formula is:
M.W. 321.8
Each 5 mL (1 teaspoon) of DILAUDID ORAL LIQUID contains 5 mg of hydromorphone
hydrochloride. In addition, other ingredients include purified water, methylparaben, propylparaben,
sucrose, and glycerin. DILAUDID ORAL LIQUID may contain traces of sodium metabisulfite.
Each DILAUDID 8 mg TABLET contains 8 mg hydromorphone hydrochloride. In addition,
the tablets include lactose anhydrous, and magnesium stearate. DILAUDID 8 mg TABLET may
contain traces of sodium metabisulfite.
CLINICAL PHARMACOLOGY:
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity
of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness.
Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes,
mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. Many
of the effects described below are common to this class of mu-opioid agonist analgesics which
includes morphine, oxycodone, hydrocodone, codeine and fentanyl. In some instances, data may not
exist to distinguish the effects of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS from
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 2
those observed with other opioid analgesics. However, in the absence of data to the contrary, it is
assumed that DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS would possess all the
actions of mu-agonist opioids.
Central Nervous System:
The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate
receptors have been identified. Opioids are believed to express their pharmacological effects by
combining with these receptors.
Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.
Hydromorphone depresses the respiratory reflex by a direct effect on brain stem respiratory centers.
The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain
stem respiratory centers to increases in carbon dioxide tension.
Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not
pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
Marked mydriasis rather than miosis may be seen with hypoxia in the setting of DILAUDID overdose,.
Gastrointestinal Tract and Other Smooth Muscle: Gastric, biliary and pancreatic secretions are
decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility
associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small
intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon
are decreased, and tone may be increased to the point of spasm. The end result is constipation.
Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the
sphincter of Oddi.
Cardiovascular System: Hydromorphone may produce hypotension as a result of either peripheral
vasodilation or release of histamine, or both. Other manifestations of histamine release and/or
peripheral vasodilation may include pruritus, flushing, and red eyes.
PHARMACOKINETICS AND METABOLISM:
The analgesic activity of DILAUDID (hydromorphone hydrochloride) is due to the parent drug,
hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract after oral
administration and undergoes extensive first-pass metabolism. Exposure of hydromorphone (Cmax and
AUC0-24) is dose-proportional at a dose range of 2 and 8 mg. In vivo bioavailability following single-
dose administration of the 8 mg tablet is approximately 24% (coefficient of variation 21%).
Bioequivalence between the DILAUDID 8 mg TABLET and an equivalent dose of DILAUDID ORAL
LIQUID has been demonstrated.
Absorption: After oral administration of DILAUDID 8 mg liquid or tablets, peak plasma
hydromorphone concentrations are generally attained within ½ to 1-hour.
Mean (%cv)
Cmax
Tmax
AUC
T½
Dosage Form
(ng)
(hrs)
(ng*hr/mL)
(hrs)
8 mg Tablet
5.5
(33%)
0.74 (34%)
23.7 (28%)
2.6
(18%)
8 mg Oral Liquid
5.7
(31%)
0.73 (71%)
24.6 (29%)
2.8
(20%)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 3
Food effects: In a study conducted with a single 8 mg dose of hydromorphone (2 mg DILAUDID® IR
tablets), food lowered Cmax by 25%, prolonged Tmax by 0.8 hour, and increased AUC by 35%. The
effects may not be clinically relevant.
Distribution: At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma
proteins. After an intravenous bolus dose, the steady state of volume distribution [mean (%cv)] is
302.9 (32%) liters.
Metabolism: Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater
than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-
hydroxy reduction metabolites.
Elimination: Only a small amount of the hydromorphone dose is excreted unchanged in the urine.
Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy
reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The
terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.
Special Populations:
Hepatic Impairment: After oral administration of hydromorphone at a single 4 mg dose (2 mg
Dilaudid IR Tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4-fold in
patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal
hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic
impairment should be started at a lower dose and closely monitored during dose titration.
Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied.
Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose
should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE
and ADMINISTRATION.
Renal Impairment: After oral administration of hydromorphone at a single 4 mg dose ( 2 mg Dilaudid
IR Tablets), exposure to hydromorphone ( Cmax and AUC0-48) is increased in patients with impaired
renal function by 2-fold in moderate (CLcr = 40 - 60 mL/min) and 3-fold in severe (CLcr < 30
mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in
patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with
longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr).
Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients
with severe renal impairment should be even lower. Patients with renal impairment should be closely
monitored during dose titration. Use of oral liquid is recommended to adjust the dose (see DOSAGE
and ADMINISTRATION).
.
Pediatrics: Pharmacokinetics of hydromorphone have not been evaluated in children.
Geriatric: Age has no effect on the pharmacokinetics of hydromorphone.
Gender: Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have
higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may
not be clinically relevant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 4
Pregnancy and nursing mothers: Hydromorphone crosses the placenta. Hydromorphone is also
found in low levels in breast milk, and may cause respiratory compromise in newborns when
administered during labor or delivery.
CLINICAL TRIALS:
Analgesic effects of single doses of DILAUDID ORAL LIQUID administered to patients with
post-surgical pain have been studied in double-blind controlled trials. In one study , both 5 mg and 10
mg of DILAUDID ORAL LIQUID provided significantly more analgesia than placebo. In another
trial, 5 mg and 10 mg of DILAUDID ORAL LIQUID were compared to 30 mg and 60 mg of morphine
sulfate oral liquid. The pain relief provided by 5 mg and 10 mg DILAUDID ORAL LIQUID was
comparable to 30 mg and 60 mg oral morphine sulfate, respectively.
INDICATIONS AND USAGE:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are indicated for the
management of pain in patients where an opioid analgesic is appropriate.
CONTRAINDICATIONS:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are contraindicated in: patients
with known hypersensitivity to hydromorphone, patients with respiratory depression in the absence of
resuscitative equipment, and in patients with status asthmaticus. DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS are also contraindicated for use in obstetrical analgesia.
WARNINGS:
Respiratory Depression: Respiratory depression is the chief hazard of DILAUDID ORAL LIQUID
and DILAUDID 8 mg TABLETS. Respiratory depression is more likely to occur in the elderly, in the
debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even
moderate therapeutic doses may dangerously decrease pulmonary ventilation.
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be used with extreme caution in
patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially
decreased respiratory reserve, hypoxia, hypercapnia, or in patients with preexisting respiratory
depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory
drive while simultaneously increasing airway resistance to the point of apnea.
DILAUDID ORAL LIQUID and DILAUDID 8mg TABLETS contain hydromorphone, which is
a potent Schedule II controlled opioid agonist. Schedule II opioid agonists, including morphine,
oxymorphone, oxycodone, fentanyl, and methadone, have the highest potential for abuse and
risk of producing respiratory depression. Alcohol, other opioids and central nervous system
depressants (sedative-hypnotics) potentiate the respiratory depressant effects of
hydromorphone, increasing the risk of respiratory depression that might result in death.
Misuse, Abuse, and Diversion of Opioids:
Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and
people with addiction disorders and are subject to criminal diversion.
DILAUDID can be abused in a manner similar to other opioid agonists, legal or illicit. This should be
considered when prescribing or dispensing DILAUDID in situations where the physician or
pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 5
monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients
should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy.
Persons at increased risk for opioid abuse include those with a personal or family history of substance
abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be
appropriate for use in these patients, however, they will require intensive monitoring for signs of
abuse.
DILAUDID has been reported as being abused by crushing, chewing, snorting, or injecting the
dissolved product. These practices pose a significant risk to the abuser that could result in overdose or
death (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled
Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse:
Hydromorphone may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression.
Neonatal Withdrawal Syndrome: Infants born to mothers physically dependent on DILAUDID will
also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see
DRUG ABUSE AND DEPENDENCE).
Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of DILAUDID
ORAL LIQUID and DILAUDID 8 mg TABLETS with carbon dioxide retention and secondary
elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury,
other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including
DILAUDID® ORAL LIQUID and DILAUDID 8 mg TABLETS (hydromorphone hydrochloride) may
produce effects on pupillary response and consciousness which can obscure the clinical course and
neurologic signs of further increase in intracranial pressure in patients with head injuries.
Hypotensive Effect: Opioid analgesics, including DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS, may cause severe hypotension in an individual whose ability to maintain blood pressure
has already been compromised by a depleted blood volume, or a concurrent administration of drugs
such as phenothiazines or general anesthetics (see PRECAUTIONS Drug Interactions). Therefore,
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be administered with caution to
patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac
output and blood pressure.
Sulfites: Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible
people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably
low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 6
PRECAUTIONS:
Special Risk Patients: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be
given with caution and the initial dose should be reduced in the elderly or debilitated and those with
severe impairment of hepatic, pulmonary or renal functions; myxedema or hypothyroidism;
adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses;
prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens;
kyphoscoliosis or following gastrointestinal surgery.
The administration of opioid analgesics including DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS may obscure the diagnoses or clinical course in patients with acute
abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders.
Reports of mild to severe seizures and myoclonus have been reported in severely compromised
patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid
administration at very high doses is associated with seizures and myoclonus in a variety of diseases
where pain control is the primary focus.
Use in Drug and Alcohol Dependent Patients : DILAUDID should be used with caution in patients
with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance,
dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID in
combination with other CNS depressant drugs can result in serious risk to the patient.
Hydromorphone is an opioid with no approved use in the management of addictive disorders.
Use in Ambulatory Patients: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS may
impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g.
driving, operating machinery). Patients should be cautioned accordingly. DILAUDID may produce
orthostatic hypotension in ambulatory patients.
Use in Biliary Tract Disease: Opioid analgesics, including DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS, should also be used with caution in patients about to undergo surgery of
the biliary tract since it may cause spasm of the sphincter of Oddi.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in
the absence of disease progression or other external factors). Physical dependence is manifested by
withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.
Physical dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other
symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
In general, opioids used regularly should not be abruptly discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-891/S-008
NDA 19-892/S-009
Page 7
Information for Patients/Caregivers
Patients receiving DILAUDID (hydromorphone hydrochloride) ORAL LIQUID or DILAUDID 8 mg
TABLETS or their caregivers should be given the following information by the physician, nurse, or
pharmacist:
1. Patients should be aware that DILAUDID tablets contain hydromorphone, which is a morphine-
like substance and which could cause severe adverse effects including respiratory depression and
even death if not taken according to the prescriber’s directions.
2. Patients should be advised to report pain and adverse experiences occurring during therapy.
Individualization of dosage is essential to make optimal use of this medication.
3. Patients should be advised not to adjust the dose of DILAUDID without consulting the prescribing
professional.
4. Patients should be advised that DILAUDID may impair mental and/or physical ability required for
the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
5. Patients should not combine DILAUDID with alcohol or other central nervous system depressants
(sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous
additive effects may occur, resulting in serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant should be
advised to consult their physician regarding the effects of analgesics and other drug use during
pregnancy on themselves and their unborn child.
7. Patients should be advised that DILAUDID is a potential drug of abuse. They should protect it
from theft, and it should never be given to anyone other than the individual for whom it was
prescribed.
8. Patients should be advised that if they have been receiving treatment with DILAUDID for more
than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the
DILAUDID dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal
symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of
the medication.
9. Patients should be instructed to keep DILAUDID in a secure place out of the reach of children.
When DILAUDID is no longer needed, the unused tablets should be destroyed by flushing down
the toilet.
Drug Interactions
Drug Interactions with Other CNS Depressants: The concomitant use of other central nervous
system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers
and alcohol may produce additive depressant effects. Respiratory depression, hypotension and
profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one
or both agents should be reduced. DILAUDID should not be taken with alcohol. Opioid analgesics,
including DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS, may enhance the action of
neuromuscular blocking agents and produce an excessive degree of respiratory depression.
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Page 8
Interactions with Mixed Agonist/Antagonist Opioid
Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should
be administered with caution to a patient who has received or is receiving a course of therapy with a
pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist
analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal
symptoms in these patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No carcinogenicity studies have been conducted in animals.
Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay or the human
lymphocyte chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse
micronucleus assay.
No effects on fertility, reproductive performance, or reproductive organ morphology were
observed y in male or female rats given oral doses up to 7 mg/kg/day, which is equivalent to the
human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of
2-4 mg every 4 to 6 hours for the tablet on a body surface area basis..
PREGNANCY-PREGNANCY CATEGORY C: No effects on teratogenicity or embryotoxicity were
observed in female rats given oral doses up to 7 mg/kg/day, which is approximately equivalent to the
human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of
2-4 mg every 4 to 6 hours for the tablet on a body surface area basis. Hydromorphone produced skull
malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg
during the peak of organogenesis (gestation days 8-9). The skull malformations were observed at
doses approximately 2-fold higher the human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and
7-fold higher than the human dose of 2-4 mg every 4 to 6 hours for the tablet on a body surface area
basis. There are no adequate and well-controlled studies of DILAUDID in pregnant women.
Hydromorphone crosses the placenta, resulting in fetal exposure. DILAUDID ORAL LIQUID
and DILAUDID 8 mg TABLETS should be used in pregnant women only if the potential benefit
justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND
DEPENDENCE).
Nonteratogenic effects: Babies born to mothers who have been taking opioids regularly prior to
delivery will be physically dependent. The withdrawal signs include irritability and excessive crying,
tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning,
vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of
maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.
Approaches to the treatment of this syndrome have included supportive care and, when indicated,
drugs such as paregoric or phenobarbital.
Labor and Delivery: DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are
contraindicated in Labor and Delivery (see CONTRAINDICATIONS).
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NDA 19-891/S-008
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Page 9
Nursing Mothers: Low levels of opioid analgesics have been detected in human milk. As a general
rule, nursing should not be undertaken while a patient is receiving DILAUDID ORAL LIQUID and
DILAUDID 8 mg TABLETS since it, and other drugs in this class, may be excreted in the milk.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: Clinical studies of DILAUDID did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy (see INDIVIDUALIZATION OF DOSAGES and PRECAUTIONS).
ADVERSE REACTIONS:
The major hazards of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS include
respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock
and cardiac arrest have occurred.
The most frequently observed adverse effects are light-headedness, dizziness, sedation, nausea,
vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be
more prominent in ambulatory patients and in those not experiencing severe pain.
Less Frequently Observed Adverse Reactions:
General and CNS: Weakness, headache, agitation, tremor, uncoordinated muscle movements,
alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity,
paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and
disorientation, visual disturbances, insomnia, increased intracranial pressure
Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope,
hypotension, hypertension.
Respiratory: Bronchospasm and laryngospasm
Gastrointestinal: Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps, taste alteration
Genitourinary: Urinary retention or hesitancy, antidiuretic effects
Dermatologic: Urticaria, other skin rashes, diaphoresis.
OVERDOSAGE:
Serious overdosage with DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS is
characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle
flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In
serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac
arrest and death may occur.
In the treatment of overdosage, primary attention should be given to the reestablishment of
adequate respiratory exchange through provision of a patent airway and institution of assisted or
controlled ventilation. A potentially serious oral ingestion, if recent, should be managed with gut
decontamination. In unconscious patients with a secure airway, instill activated charcoal (30-100 g in
adults, 1-2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the
first dose of activated charcoal.
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Page 10
Supportive measures (including oxygen, vasopressors) should be employed in the management
of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or
arrhythmias may require cardiac massage or defibrillation.
The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result
from overdosage, or unusual sensitivity to DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS. Therefore, an appropriate dose of this antagonist should be administered, preferably by the
intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be
administered in the absence of clinically significant respiratory or circulatory depression. Naloxone
should be administered cautiously to persons who are known, or suspected to be physically dependent
on DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS . In such cases, an abrupt or
complete reversal of narcotic effects may precipitate an acute withdrawal syndrome. Since the duration
of action of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS may exceed that of the
antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist
may be required to maintain adequate respiration. Apply other supportive measures when indicated.
DOSAGE AND ADMINISTRATION:
DILAUDID ORAL LIQUID: The usual adult oral dosage of DILAUDID ORAL LIQUID is one-half
(2.5 mL) to two teaspoonfuls (10 mL) (2.5 mg - 10 mg) every 3 to 6 hours as directed by the clinical
situation. Oral dosages higher than the usual dosages may be required in some patients.
DILAUDID 8 mg TABLET: The usual starting dose for DILAUDID tablets is 2 mg to 4 mg, orally,
every 4 to 6 hours. Appropriate use of the DILAUDID 8 mg TABLET must be decided by careful
evaluation of each clinical situation.
A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or
if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.
Patients with hepatic and renal impairment should be started on a lower starting dose (See
CLINCIAL PHARMCOLOGY :PHARMACOKINETICS and METABOLISM).
INDIVIDUALIZATION OF DOSAGE:
The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized
for any given patient, since adverse events can occur at doses that may not provide complete freedom
from pain.
Safe and effective administration of opioid analgesics to patients with acute or chronic pain
depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency,
etiology, and pathophysiology) as well as the concurrent medical status of the patient will affect
selection of the starting dosage.
In non-opioid-tolerant patients, therapy with hydromorphone is typically initiated at an oral
dose of 2-4 mg every four hours, but elderly patients may require lower doses (see PRECAUTIONS -
Geriatric Use).
In patients receiving opioids, both the dose and duration of analgesia will vary substantially
depending on the patient's opioid tolerance. The dose should be selected and adjusted so that at least 3-
4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of
DILAUDID should be based on prior opioid usage. This should be done by converting the total daily
usage of the previous opioid to an equivalent total daily dosage of oral DILAUDID using an
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NDA 19-891/S-008
NDA 19-892/S-009
Page 11
equianalgesic table (see below). For opioids not in the table, first estimate the equivalent total daily
usage of oral morphine, then use the table to find the equivalent total daily dosage of DILAUDID.
Once the total daily dosage of DILAUDID has been estimated, it should be divided into the
desired number of doses. Since there is individual variation in response to different opioid drugs, only
1/2 to 2/3 of the estimated dose of DILAUDID calculated from equivalence tables should be given for
the first few doses, then increased as needed according to the patient's response.
Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment
with a consequent increase in exposure, Patients with hepatic and renal impairment should be started
on a lower starting dose (See CLINCIAL PHARMCOLOGY :PHARMCOKINETICS and
METABOLISM).
In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5-15%
of the total daily usage may be administered every two hours on an "as-needed" basis.
Periodic reassessment after the initial dosing is always required. If pain management is not
satisfactory and in the absence of significant opioid-induced adverse events, the hydromorphone dose
may be increased gradually. If excessive opioid side effects are observed early in the dosing interval,
the hydromorphone dose should be reduced. If this results in breakthrough pain at the end of the dosing
interval, the dosing interval may need to be shortened. Dose titration should be guided more by the
need for analgesia than the absolute dose of opioid employed.
OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC POTENCY*
Nonproprietary
(Trade) Name
IM or SC
Dose
ORAL
Dose
Morphine sulfate
10mg
40-60mg
Hydromorphone HCl
(DILAUDID)
1.3-2mg
6.5-7.5mg
Oxymorphone HCl
(Numorphan)
1-1.1mg
6.6mg
Levorphanol tartrate
(Levo-Dromoran)
2-2.3mg
4mg
Meperidine, pethidine HCl
(Demerol)
75-100mg
300-400mg
Methadone HCl
(Dolophine)
10mg
10-20mg
* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references
comparing opioid analgesics in cancer and severe pain.
DRUG ABUSE AND DEPENDENCE
DILAUDID ORAL LIQUID and DILAUDID 8 MG TABLETS contain hydromorphone, a
Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine,
oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk
of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion.
Opioid analgesics may cause psychological and physical dependence. Physical dependence
results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical
dependence usually does not occur to a clinically significant degree until after several weeks of
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NDA 19-892/S-009
Page 12
continued opioid usage, but it may occur after as little as a week of opioid use. Physical
dependence and tolerance are separate and distinct from abuse and addiction.
Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors
influencing its development and manifestations. It is characterized by behaviors that include one or
more of the following: impaired control over drug use, compulsive use, continued use despite harm,
and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is
common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include
emergency calls or visits near the end of office hours, refusal to undergo appropriate examination,
testing or referral, repeated “loss” of prescriptions, tampering with, forging or counterfeiting
prescriptions and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers,
people suffering from untreated addiction and criminals seeking drugs to sell.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of addiction and is characterized by misuse for non-medical purposes, often in combination
with other psychoactive substances. Since DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS may be diverted for non-medical use, careful record keeping of prescribing information,
including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and
proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS are intended for oral use only. Misuse
or abuse of DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS pose a risk of overdose and
death. This risk is increased with concurrent abuse of alcohol and other CNS depressants. Parenteral
drug abuse can potentially result in local tissue necrosis, infection, pulmonary granulomas, and
increased risk of endocarditis and valvular heart injury. In addition, parenteral abuse is commonly
associated with transmission of infectious diseases such as hepatitis and HIV.
SAFETY AND HANDLING INSTRUCTIONS:
DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS pose little risk of direct
exposure to health care personnel and should be handled and disposed of prudently in accordance with
hospital or institutional policy. Significant absorption from dermal exposure is unlikely; accidental
dermal exposure to DILAUDID ORAL LIQUID should be treated by removal of any contaminated
clothing and rinsing the affected area with cool water. Patients and their families should be instructed
to flush any DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS that are no longer needed.
Access to abuseable drugs such as DILAUDID ORAL LIQUID and DILAUDID 8 mg
TABLETS presents an occupational hazard for addiction in the health care industry. Routine
procedures for handling controlled substances developed to protect the public may not be adequate to
protect health care workers. Implementation of more effective accounting procedures and measures to
restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-
administration by health care providers.
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Page 13
HOW SUPPLIED:
DILAUDID ORAL LIQUID is a clear, sweet, slightly viscous liquid. It is available in:
Bottles of 1 pint (473 mL)-NDC# 0074-2452-02
DILAUDID 8 mg TABLETS are white and triangular shaped, embossed with the number 8 on one
side and bisected and embossed with a double
on the other side. They are available in:
Bottles of 100-NDC# 0074-2426-14
STORAGE: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled
Room Temperature]. Protect from light.
A schedule CII Narcotic. DEA Order Form is Required.
©Abbott
All rights reserved.
Revised: NEW
NEW
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|
custom-source
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2025-02-12T13:46:14.663547
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019892s009,019891s008lbl.pdf', 'application_number': 19892, 'submission_type': 'SUPPL ', 'submission_number': 9}
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11,822
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DILAUDID® ORAL LIQUID and DILAUDID® TABLETS
(hydromorphone hydrochloride)
CS-II
WARNING: DILAUDID ORAL LIQUID AND DILAUDID TABLETS CONTAIN
HYDROMORPHONE, WHICH IS A POTENT SCHEDULE II CONTROLLED OPIOID
AGONIST. SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE,
OXYMORPHONE, OXYCODONE, FENTANYL, AND METHADONE, HAVE THE
HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING RESPIRATORY
DEPRESSION. ALCOHOL, OTHER OPIOIDS AND CENTRAL NERVOUS SYSTEM
DEPRESSANTS (SEDATIVE-HYPNOTICS) POTENTIATE THE RESPIRATORY
DEPRESSANT EFFECTS OF HYDROMORPHONE, INCREASING THE RISK OF
RESPIRATORY DEPRESSION THAT MIGHT RESULT IN DEATH.
DESCRIPTION
Proprietary name:
DILAUDID ORAL LIQUID
Established name:
hydromorphone hydrochloride
Route of administration:
ORAL (C38288)
Active ingredients (moiety):
hydromorphone hydrochloride (hydromorphone)
#
Strength
Form
Inactive ingredients
1
5 MILLIGRAM
LIQUID
(C42953)
purified water, methylparaben, propylparaben, sucrose, glycerin, sodium
metabisulfite
Proprietary name:
DILAUDID TABLETS
Established name:
hydromorphone hydrochloride
Route of administration:
ORAL (C38288)
Active ingredients (moiety):
hydromorphone hydrochloride (hydromorphone)
#
Strength
Form
Inactive ingredients
1
2 MILLIGRAM
TABLET
(C42998)
D&C red #30 Lake dye, D&C yellow #10 Lake dye, lactose, magnesium
stearate, sodium metabisulfite
2
4 MILLIGRAM
TABLET
(C42998)
D&C yellow #10 Lake dye, lactose, magnesium stearate, sodium metabisulfite
3
8 MILLIGRAM
TABLET
(C42998)
lactose anhydrous, magnesium stearate, sodium metabisulfite
DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an
opioid analgesic.
The chemical name of DILAUDID (hydromorphone hydrochloride) is 4,5α-epoxy-3-
hydroxy-17-methylmorphinan-6-one hydrochloride. The structural formula is:
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M.W. 321.8
Each 5 mL (1 teaspoon) of DILAUDID ORAL LIQUID contains 5 mg of hydromorphone
hydrochloride. In addition, other ingredients include purified water, methylparaben,
propylparaben, sucrose, and glycerin. DILAUDID ORAL LIQUID may contain traces of
sodium metabisulfite.
Color Coded Tablets (for oral administration) contain:
2 mg hydromorphone hydrochloride (orange tablet) and D&C red #30 Lake dye, D&C
yellow #10 Lake dye, lactose, and magnesium stearate. DILAUDID 2 mg TABLET may
contain traces of sodium metabisulfite.
4 mg hydromorphone hydrochloride (yellow tablet) and D&C yellow #10 Lake dye, lactose,
and magnesium stearate. DILAUDID 4 mg TABLET may contain traces of sodium
metabisulfite.
8 mg hydromorphone hydrochloride (white tablet) and lactose anhydrous, and magnesium
stearate. DILAUDID 8 mg TABLET may contain traces of sodium metabisulfite.
CLINICAL PHARMACOLOGY
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic
activity of analgesia. A significant feature of the analgesia is that it can occur without loss
of consciousness. Opioid analgesics also suppress the cough reflex and may cause
respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea,
vomiting and electroencephalographic changes. Many of the effects described below are
common to this class of mu-opioid agonist analgesics which includes morphine,
oxycodone, hydrocodone, codeine and fentanyl. In some instances, data may not exist to
distinguish the effects of DILAUDID ORAL LIQUID and DILAUDID TABLETS from those
observed with other opioid analgesics. However, in the absence of data to the contrary, it
is assumed that DILAUDID ORAL LIQUID and DILAUDID TABLETS would possess all the
actions of mu-agonist opioids.
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Central Nervous System
The precise mode of analgesic action of opioid analgesics is unknown. However, specific
CNS opiate receptors have been identified. Opioids are believed to express their
pharmacological effects by combining with these receptors.
Hydromorphone depresses the cough reflex by direct effect on the cough center in the
medulla.
Hydromorphone depresses the respiratory reflex by a direct effect on brain stem
respiratory centers. The mechanism of respiratory depression also involves a reduction in
the responsiveness of the brain stem respiratory centers to increases in carbon dioxide
tension.
Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but
are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may
produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia
in the setting of DILAUDID overdose.
Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by opioids such as
hydromorphone. Hydromorphone causes a reduction in motility associated with an
increase in tone in the gastric antrum and duodenum. Digestion of food in the small
intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic
waves in the colon are decreased, and tone may be increased to the point of spasm. The
end result is constipation. Hydromorphone can cause a marked increase in biliary tract
pressure as a result of spasm of the sphincter of Oddi.
Cardiovascular System
Hydromorphone may produce hypotension as a result of either peripheral vasodilation or
release of histamine, or both. Other manifestations of histamine release and/or peripheral
vasodilation may include pruritus, flushing, and red eyes.
Pharmacokinetics and Metabolism
The analgesic activity of DILAUDID (hydromorphone hydrochloride) is due to the parent
drug, hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract
after oral administration and undergoes extensive first-pass metabolism. Exposure of
hydromorphone (Cmax and AUC0-24) is dose-proportional at a dose range of 2 and 8 mg. In
vivo bioavailability following single-dose administration of the 8 mg tablet is approximately
24% (coefficient of variation 21%). Bioequivalence between the DILAUDID 8 mg TABLET
and an equivalent dose of DILAUDID ORAL LIQUID has been demonstrated.
Absorption
After oral administration of DILAUDID 8 mg liquid or tablets, peak plasma hydromorphone
concentrations are generally attained within ½ to 1-hour.
Mean (%cv)
Dosage Form
C max
(ng)
T max
(hrs)
AUC
(ng*hr/mL)
T ½
(hrs)
8 mg Tablet
5.5
(33%)
0.74
(34%)
23.7
(28%)
2.6
(18%)
8 mg Oral Liquid
5.7
(31%)
0.73
(71%)
24.6
(29%)
2.8
(20%)
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Food Effects
In a study conducted with a single 8 mg dose of hydromorphone (2 mg DILAUDID® IR
tablets), food lowered Cmax by 25%, prolonged Tmax by 0.8 hour, and increased AUC by
35%. The effects may not be clinically relevant.
Distribution
At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma
proteins. After an intravenous bolus dose, the steady state of volume distribution [mean
(%cv)] is 302.9 (32%) liters.
Metabolism
Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater
than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor
amounts of 6-hydroxy reduction metabolites.
Elimination
Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most
of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-
hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%)
liters/minute. The terminal elimination half-life of hydromorphone after an intravenous
dose is about 2.3 hours.
Special Populations
Hepatic Impairment
After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR
Tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4-fold in
patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects
with normal hepatic function. Due to increased exposure of hydromorphone, patients with
moderate hepatic impairment should be started at a lower dose and closely monitored
during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment
patients has not been studied. Further increase in Cmax and AUC of hydromorphone in this
group is expected. As such, starting dose should be even more conservative. Use of oral
liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION ).
Renal Impairment
After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR
Tablets), exposure to hydromorphone ( Cmax and AUC0-48) is increased in patients with
impaired renal function by 2-fold in moderate (CLcr = 40 - 60 mL/min) and 3-fold in severe
(CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min).
In addition, in patients with severe renal impairment hydromorphone appeared to be more
slowly eliminated with longer terminal elimination half-life (40 hr) compared to patients with
normal renal function (15 hr). Patients with moderate renal impairment should be started
on a lower dose. Starting doses for patients with severe renal impairment should be even
lower. Patients with renal impairment should be closely monitored during dose titration.
Use of oral liquid is recommended to adjust the dose (see DOSAGE AND
ADMINISTRATION).
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Pediatrics
Pharmacokinetics of hydromorphone have not been evaluated in children.
Geriatric
Age has no effect on the pharmacokinetics of hydromorphone.
Gender
Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to
have higher Cmax (25%) than males with comparable AUC0-24 values. The difference
observed in Cmax may not be clinically relevant.
Pregnancy and Nursing Mothers
Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in
breast milk, and may cause respiratory compromise in newborns when administered
during labor or delivery.
CLINICAL TRIALS
Analgesic effects of single doses of DILAUDID ORAL LIQUID administered to patients
with post-surgical pain have been studied in double-blind controlled trials. In one study,
both 5 mg and 10 mg of DILAUDID ORAL LIQUID provided significantly more analgesia
than placebo. In another trial, 5 mg and 10 mg of DILAUDID ORAL LIQUID were
compared to 30 mg and 60 mg of morphine sulfate oral liquid. The pain relief provided by
5 mg and 10 mg DILAUDID ORAL LIQUID was comparable to 30 mg and 60 mg oral
morphine sulfate, respectively.
INDICATIONS AND USAGE
DILAUDID ORAL LIQUID and DILAUDID TABLETS are indicated for the management of
pain in patients where an opioid analgesic is appropriate.
CONTRAINDICATIONS
DILAUDID ORAL LIQUID and DILAUDID TABLETS are contraindicated in: patients with
known hypersensitivity to hydromorphone, patients with respiratory depression in the
absence of resuscitative equipment, and in patients with status asthmaticus. DILAUDID
ORAL LIQUID and DILAUDID TABLETS are also contraindicated for use in obstetrical
analgesia.
WARNINGS
Respiratory Depression
Respiratory depression is the chief hazard of DILAUDID ORAL LIQUID and DILAUDID
TABLETS. Respiratory depression is more likely to occur in the elderly, in the debilitated,
and in those suffering from conditions accompanied by hypoxia or hypercapnia when even
moderate therapeutic doses may dangerously decrease pulmonary ventilation.
DILAUDID ORAL LIQUID and DILAUDID TABLETS should be used with extreme caution
in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
substantially decreased respiratory reserve, hypoxia, hypercapnia, or in patients with
preexisting respiratory depression. In such patients even usual therapeutic doses of opioid
analgesics may decrease respiratory drive while simultaneously increasing airway
resistance to the point of apnea.
DILAUDID ORAL LIQUID and DILAUDID TABLETS contain hydromorphone, which is
a potent Schedule II controlled opioid agonist. Schedule II opioid agonists,
including morphine, oxymorphone, oxycodone, fentanyl, and methadone, have the
highest potential for abuse and risk of producing respiratory depression. Alcohol,
other opioids and central nervous system depressants (sedative-hypnotics)
potentiate the respiratory depressant effects of hydromorphone, increasing the risk
of respiratory depression that might result in death.
Misuse, Abuse, and Diversion of Opioids
Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug
abusers and people with addiction disorders and are subject to criminal diversion.
DILAUDID can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing DILAUDID in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or
diversion. Prescribers should monitor all patients receiving opioids for signs of abuse,
misuse, and addiction. Furthermore, patients should be assessed for their potential for
opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid
abuse include those with a personal or family history of substance abuse (including drug
or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for
use in these patients, however, they will require intensive monitoring for signs of abuse
DILAUDID has been reported as being abused by crushing, chewing, snorting, or injecting
the dissolved product. These practices pose a significant risk to the abuser that could
result in overdose or death (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Concerns about abuse, addiction, and diversion should not prevent the proper
management of pain.
Healthcare professionals should contact their State Professional Licensing Board or State
Controlled Substances Authority for information on how to prevent and detect abuse or
diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Hydromorphone may be expected to have additive effects when used in conjunction with
alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Neonatal Withdrawal Syndrome
Infants born to mothers physically dependent on DILAUDID will also be physically
dependent and may exhibit respiratory difficulties and withdrawal symptoms (see DRUG
ABUSE AND DEPENDENCE ).
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of DILAUDID ORAL LIQUID and DILAUDID TABLETS
with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may
be markedly exaggerated in the presence of head injury, other intracranial lesions, or
preexisting increase in intracranial pressure. Opioid analgesics including DILAUDID ORAL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LIQUID and DILAUDID TABLETS (hydromorphone hydrochloride) may produce effects on
pupillary response and consciousness which can obscure the clinical course and
neurologic signs of further increase in intracranial pressure in patients with head injuries.
Hypotensive Effect
Opioid analgesics, including DILAUDID ORAL LIQUID and DILAUDID TABLETS, may
cause severe hypotension in an individual whose ability to maintain blood pressure has
already been compromised by a depleted blood volume, or a concurrent administration of
drugs such as phenothiazines or general anesthetics (see PRECAUTIONS - Drug
Interactions ). Therefore, DILAUDID ORAL LIQUID and DILAUDID TABLETS should be
administered with caution to patients in circulatory shock, since vasodilation produced by
the drug may further reduce cardiac output and blood pressure.
Sulfites
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain
susceptible people. The overall prevalence of sulfite sensitivity in the general population is
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in
nonasthmatic people.
PRECAUTIONS
Special Risk Patients
DILAUDID ORAL LIQUID and DILAUDID TABLETS should be given with caution and the
initial dose should be reduced in the elderly or debilitated and those with severe
impairment of hepatic, pulmonary or renal functions; myxedema or hypothyroidism;
adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic
psychoses; prostatic hypertrophy or urethral stricture; gall bladder disease; acute
alcoholism; delirium tremens; kyphoscoliosis or following gastrointestinal surgery.
The administration of opioid analgesics including DILAUDID ORAL LIQUID and DILAUDID
TABLETS may obscure the diagnoses or clinical course in patients with acute abdominal
conditions and may aggravate preexisting convulsions in patients with convulsive
disorders.
Reports of mild to severe seizures and myoclonus have been reported in severely
compromised patients, administered high doses of parenteral hydromorphone, for cancer
and severe pain. Opioid administration at very high doses is associated with seizures and
myoclonus in a variety of diseases where pain control is the primary focus.
Use in Drug and Alcohol Dependent Patients
DILAUDID should be used with caution in patients with alcoholism and other drug
dependencies due to the increased frequency of opioid tolerance, dependence, and the
risk of addiction observed in these patient populations. Abuse of DILAUDID in combination
with other CNS depressant drugs can result in serious risk to the patient.
Hydromorphone is an opioid with no approved use in the management of addictive
disorders.
Use in Ambulatory Patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DILAUDID ORAL LIQUID and DILAUDID TABLETS may impair mental and/or physical
ability required for the performance of potentially hazardous tasks (e.g. driving, operating
machinery). Patients should be cautioned accordingly. DILAUDID may produce orthostatic
hypotension in ambulatory patients.
Use in Biliary Tract Disease
Opioid analgesics, including DILAUDID ORAL LIQUID and DILAUDID TABLETS, should
also be used with caution in patients about to undergo surgery of the biliary tract since it
may cause spasm of the sphincter of Oddi.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as
analgesia (in the absence of disease progression or other external factors). Physical
dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug
or upon administration of an antagonist. Physical dependence and tolerance are not
unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the
following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia,
mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache,
joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea,
or increased blood pressure, respiratory rate, or heart rate.
In general, opioids used regularly should not be abruptly discontinued.
Information for Patients/Caregivers
Patients receiving DILAUDID (hydromorphone hydrochloride) ORAL LIQUID or DILAUDID
TABLETS or their caregivers should be given the following information by the physician,
nurse, or pharmacist:
1. Patients should be aware that DILAUDID tablets contain hydromorphone, which is
a morphine-like substance and which could cause severe adverse effects including
respiratory depression and even death if not taken according to the prescriber’s
directions.
2. Patients should be advised to report pain and adverse experiences occurring
during therapy. Individualization of dosage is essential to make optimal use of this
medication.
3. Patients should be advised not to adjust the dose of DILAUDID without consulting
the prescribing professional.
4. Patients should be advised that DILAUDID may impair mental and/or physical
ability required for the performance of potentially hazardous tasks (e.g., driving,
operating heavy machinery).
5. Patients should not combine DILAUDID with alcohol or other central nervous
system depressants (sleep aids, tranquilizers) except by the orders of the
prescribing physician, because dangerous additive effects may occur, resulting in
serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant
should be advised to consult their physician regarding the effects of analgesics and
other drug use during pregnancy on themselves and their unborn child.
7. Patients should be advised that DILAUDID is a potential drug of abuse. They
should protect it from theft, and it should never be given to anyone other than the
individual for whom it was prescribed.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8. Patients should be advised that if they have been receiving treatment with
DILAUDID for more than a few weeks and cessation of therapy is indicated, it may
be appropriate to taper the DILAUDID dose, rather than abruptly discontinue it, due
to the risk of precipitating withdrawal symptoms. Their physician can provide a dose
schedule to accomplish a gradual discontinuation of the medication.
9. Patients should be instructed to keep DILAUDID in a secure place out of the reach
of children. When DILAUDID is no longer needed, the unused tablets should be
destroyed by flushing down the toilet.
Drug Interactions
Drug Interactions with Other CNS Depressants
The concomitant use of other central nervous system depressants including sedatives or
hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce
additive depressant effects. Respiratory depression, hypotension and profound sedation
or coma may occur. When such combined therapy is contemplated, the dose of one or
both agents should be reduced. DILAUDID should not be taken with alcohol. Opioid
analgesics, including DILAUDID ORAL LIQUID and DILAUDID TABLETS, may enhance
the action of neuromuscular blocking agents and produce an excessive degree of
respiratory depression.
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and
buprenorphine) should be administered with caution to a patient who has received or is
receiving a course of therapy with a pure opioid agonist analgesic such as
hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the
analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these
patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies have been conducted in animals.
Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay or the
human lymphocyte chromosome aberration assay. Hydromorphone was not clastogenic in
the in vivo mouse micronucleus assay.
No effects on fertility, reproductive performance, or reproductive organ morphology were
observed in male or female rats given oral doses up to 7 mg/kg/day, which is equivalent to
the human dose of 2.5-10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the
human dose of 2-4 mg every 4 to 6 hours for the tablet on a body surface area basis.
Pregnancy
Pregnancy Category C
No effects on teratogenicity or embryotoxicity were observed in female rats given oral
doses up to 7 mg/kg/day, which is approximately equivalent to the human dose of 2.5-10
mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of 2-4 mg
every 4 to 6 hours for the tablet on a body surface area basis. Hydromorphone produced
skull malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses
up to 20 mg/kg during the peak of organogenesis (gestation days 8-9). The skull
malformations were observed at doses approximately 2-fold higher the human dose of
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5-10 mg every 3 to 6 hours for oral liquid, and 7-fold higher than the human dose of 2-4
mg every 4 to 6 hours for the tablet on a body surface area basis. There are no adequate
and well-controlled studies of DILAUDID in pregnant women.
Hydromorphone crosses the placenta, resulting in fetal exposure. DILAUDID ORAL
LIQUID and DILAUDID TABLETS should be used in pregnant women only if the potential
benefit justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE
AND DEPENDENCE ).
Nonteratogenic Effects
Babies born to mothers who have been taking opioids regularly prior to delivery will be
physically dependent. The withdrawal signs include irritability and excessive crying,
tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing,
yawning, vomiting, and fever. The intensity of the syndrome does not always correlate
with the duration of maternal opioid use or dose. There is no consensus on the best
method of managing withdrawal. Approaches to the treatment of this syndrome have
included supportive care and, when indicated, drugs such as paregoric or phenobarbital.
Labor and Delivery
DILAUDID ORAL LIQUID and DILAUDID TABLETS are contraindicated in Labor and
Delivery (see CONTRAINDICATIONS).
Nursing Mothers
Low levels of opioid analgesics have been detected in human milk. As a general rule,
nursing should not be undertaken while a patient is receiving DILAUDID ORAL LIQUID
and DILAUDID TABLETS since it, and other drugs in this class, may be excreted in the
milk.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical studies of DILAUDID did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy (see INDIVIDUALIZATION OF
DOSAGES and PRECAUTIONS).
ADVERSE REACTIONS
The major hazards of DILAUDID ORAL LIQUID and DILAUDID TABLETS include
respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory
arrest, shock and cardiac arrest have occurred.
The most frequently observed adverse effects are light-headedness, dizziness, sedation,
nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These
effects seem to be more prominent in ambulatory patients and in those not experiencing
severe pain.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Less Frequently Observed Adverse Reactions
General and CNS
Weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of
mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity,
paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient
hallucinations and disorientation, visual disturbances, insomnia, increased intracranial
pressure
Cardiovascular
Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope,
hypotension, hypertension
Respiratory
Bronchospasm and laryngospasm
Gastrointestinal
Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps, taste alteration
Genitourinary
Urinary retention or hesitancy, antidiuretic effects
Dermatologic
Urticaria, other skin rashes, diaphoresis
OVERDOSAGE
Serious overdosage with DILAUDID ORAL LIQUID and DILAUDID TABLETS is
characterized by respiratory depression, somnolence progressing to stupor or coma,
skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes
bradycardia and hypotension. In serious overdosage, particularly following intravenous
injection, apnea, circulatory collapse, cardiac arrest and death may occur.
In the treatment of overdosage, primary attention should be given to the reestablishment
of adequate respiratory exchange through provision of a patent airway and institution of
assisted or controlled ventilation. A potentially serious oral ingestion, if recent, should be
managed with gut decontamination. In unconscious patients with a secure airway, instill
activated charcoal (30-100 g in adults, 1-2 g/kg in infants) via a nasogastric tube. A saline
cathartic or sorbitol may be added to the first dose of activated charcoal.
Supportive measures (including oxygen, vasopressors) should be employed in the
management of circulatory shock and pulmonary edema accompanying overdose as
indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
The opioid antagonist, naloxone, is a specific antidote against respiratory depression
which may result from overdosage, or unusual sensitivity to DILAUDID ORAL LIQUID and
DILAUDID TABLETS. Therefore, an appropriate dose of this antagonist should be
administered, preferably by the intravenous route, simultaneously with efforts at
respiratory resuscitation. Naloxone should not be administered in the absence of clinically
significant respiratory or circulatory depression. Naloxone should be administered
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For current labeling information, please visit https://www.fda.gov/drugsatfda
cautiously to persons who are known, or suspected to be physically dependent on
DILAUDID ORAL LIQUID and DILAUDID TABLETS. In such cases, an abrupt or complete
reversal of narcotic effects may precipitate an acute withdrawal syndrome. Since the
duration of action of DILAUDID ORAL LIQUID and DILAUDID TABLETS may exceed that
of the antagonist, the patient should be kept under continued surveillance; repeated doses
of the antagonist may be required to maintain adequate respiration. Apply other supportive
measures when indicated.
DOSAGE AND ADMINISTRATION
Dilaudid Oral Liquid
The usual adult oral dosage of DILAUDID ORAL LIQUID is one-half (2.5 mL) to two
teaspoonfuls (10 mL) (2.5 mg - 10 mg) every 3 to 6 hours as directed by the clinical
situation. Oral dosages higher than the usual dosages may be required in some patients.
Dilaudid Tablets
The usual starting dose for DILAUDID tablets is 2 mg to 4 mg, orally, every 4 to 6 hours.
Appropriate use of the DILAUDID TABLETS must be decided by careful evaluation of
each clinical situation.
A gradual increase in dose may be required if analgesia is inadequate, as tolerance
develops, or if pain severity increases. The first sign of tolerance is usually a reduced
duration of effect.
Patients with hepatic and renal impairment should be started on a lower starting dose
(See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism).
INDIVIDUALIZATION OF DOSAGE
The dosage of opioid analgesics like hydromorphone hydrochloride should be
individualized for any given patient, since adverse events can occur at doses that may not
provide complete freedom from pain.
Safe and effective administration of opioid analgesics to patients with acute or chronic
pain depends upon a comprehensive assessment of the patient. The nature of the pain
(severity, frequency, etiology, and pathophysiology) as well as the concurrent medical
status of the patient will affect selection of the starting dosage.
In non-opioid-tolerant patients, therapy with hydromorphone is typically initiated at an oral
dose of 2-4 mg every four hours, but elderly patients may require lower doses (see
PRECAUTIONS - Geriatric Use).
In patients receiving opioids, both the dose and duration of analgesia will vary
substantially depending on the patient's opioid tolerance. The dose should be selected
and adjusted so that at least 3-4 hours of pain relief may be achieved. In patients taking
opioid analgesics, the starting dose of DILAUDID should be based on prior opioid usage.
This should be done by converting the total daily usage of the previous opioid to an
equivalent total daily dosage of oral DILAUDID using an equianalgesic table (see below).
For opioids not in the table, first estimate the equivalent total daily usage of oral morphine,
then use the table to find the equivalent total daily dosage of DILAUDID.
Once the total daily dosage of DILAUDID has been estimated, it should be divided into the
desired number of doses. Since there is individual variation in response to different opioid
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For current labeling information, please visit https://www.fda.gov/drugsatfda
drugs, only 1/2 to 2/3 of the estimated dose of DILAUDID calculated from equivalence
tables should be given for the first few doses, then increased as needed according to the
patient's response.
Since the pharmacokinetics of hydromorphone are affected in hepatic and renal
impairment with a consequent increase in exposure, patients with hepatic and renal
impairment should be started on a lower starting dose (See CLINICAL
PHARMACOLOGY - Pharmacokinetics and Metabolism).
In chronic pain, doses should be administered around-the-clock. A supplemental dose of
5-15% of the total daily usage may be administered every two hours on an "as-needed"
basis.
Periodic reassessment after the initial dosing is always required. If pain management is
not satisfactory and in the absence of significant opioid-induced adverse events, the
hydromorphone dose may be increased gradually. If excessive opioid side effects are
observed early in the dosing interval, the hydromorphone dose should be reduced. If this
results in breakthrough pain at the end of the dosing interval, the dosing interval may need
to be shortened. Dose titration should be guided more by the need for analgesia than the
absolute dose of opioid employed.
OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC
POTENCY*
Nonproprietary
(Trade) Name
IM or SC
Dose
ORAL
Dose
Morphine sulfate
10 mg
40-60 mg
Hydromorphone HCl
(DILAUDID)
1.3-2 mg
6.5-7.5 mg
Oxymorphone HCl
(Numorphan)
1-1.1 mg
6.6 mg
Levorphanol tartrate
(Levo-Dromoran)
2-2.3 mg
4 mg
Meperidine, pethidine HCl
(Demerol)
75-100 mg
300-400 mg
Methadone HCl
(Dolophine)
10 mg
10-20 mg
* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published
references comparing opioid analgesics in cancer and severe pain.
DRUG ABUSE AND DEPENDENCE
DILAUDID ORAL LIQUID and DILAUDID TABLETS contain hydromorphone, a
Schedule II controlled opioid agonist. Schedule II opioid substances which include
morphine, oxycodone, oxymorphone, fentanyl, and methadone have the highest
potential for abuse and risk of fatal overdose. Hydromorphone can be abused and
is subject to criminal diversion.
Opioid analgesics may cause psychological and physical dependence. Physical
dependence results in withdrawal symptoms in patients who abruptly discontinue
the drug. Physical dependence usually does not occur to a clinically significant
degree until after several weeks of continued opioid usage, but it may occur after as
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For current labeling information, please visit https://www.fda.gov/drugsatfda
little as a week of opioid use. Physical dependence and tolerance are separate and
distinct from abuse and addiction.
Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized
by behaviors that include one or more of the following: impaired control over drug use,
compulsive use, continued use despite harm, and craving. Drug addiction is a treatable
disease, utilizing a multidisciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking
tactics include emergency calls or visits near the end of office hours, refusal to undergo
appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering
with, forging or counterfeiting prescriptions and reluctance to provide prior medical records
or contact information for other treating physician(s). “Doctor shopping” to obtain
additional prescriptions is common among drug abusers, people suffering from untreated
addiction and criminals seeking drugs to sell.
Physicians should be aware that addiction may not be accompanied by concurrent
tolerance and symptoms of physical dependence in all addicts. In addition, abuse of
opioids can occur in the absence of addiction and is characterized by misuse for non-
medical purposes, often in combination with other psychoactive substances. Since
DILAUDID ORAL LIQUID and DILAUDID TABLETS may be diverted for non-medical use,
careful record keeping of prescribing information, including quantity, frequency, and
renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of
therapy, and proper dispensing and storage are appropriate measures that help to limit
abuse of opioid drugs.
DILAUDID ORAL LIQUID and DILAUDID TABLETS are intended for oral use only. Misuse
or abuse of DILAUDID ORAL LIQUID and DILAUDID TABLETS pose a risk of overdose
and death. This risk is increased with concurrent abuse of alcohol and other CNS
depressants. Parenteral drug abuse can potentially result in local tissue necrosis,
infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart
injury. In addition, parenteral abuse is commonly associated with transmission of
infectious diseases such as hepatitis and HIV.
SAFETY AND HANDLING INSTRUCTIONS
DILAUDID ORAL LIQUID and DILAUDID TABLETS pose little risk of direct exposure to
health care personnel and should be handled and disposed of prudently in accordance
with hospital or institutional policy. Significant absorption from dermal exposure is unlikely;
accidental dermal exposure to DILAUDID ORAL LIQUID should be treated by removal of
any contaminated clothing and rinsing the affected area with cool water. Patients and their
families should be instructed to flush any DILAUDID ORAL LIQUID and DILAUDID
TABLETS that are no longer needed.
Access to abuseable drugs such as DILAUDID ORAL LIQUID and DILAUDID TABLETS
presents an occupational hazard for addiction in the health care industry. Routine
procedures for handling controlled substances developed to protect the public may not be
adequate to protect health care workers. Implementation of more effective accounting
procedures and measures to restrict access to drugs of this class (appropriate to the
practice setting) may minimize the risk of self-administration by health care providers.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
#
Name
Strength
Dosage
Form
Appearance
Package Type
Package Qty
NDC
1
DILAUDID
ORAL LIQUID
5 MILLIGRAM
LIQUID
(C42953)
BOTTLE
(C43169)
473 MILLILITER
0074-
2452-02
2
DILAUDID
TABLETS
2 MILLIGRAM
TABLET
(C42998)
BOTTLE
(C43169)
100 TABLET
0074-
2415-14
2
DILAUDID
TABLETS
2 MILLIGRAM
TABLET
(C42998)
BLISTER PACK
(C43168)
25 TABLET
3
DILAUDID
TABLETS
4 MILLIGRAM
TABLET
(C42998)
BOTTLE
(C43169)
100 TABLET
0074-
2416-14
3
DILAUDID
TABLETS
4 MILLIGRAM
TABLET
(C42998)
BOTTLE
(C43169)
500 TABLET
0074-
2416-54
3
DILAUDID
TABLETS
4 MILLIGRAM
TABLET
(C42998)
BLISTER PACK
(C43168)
25 TABLET
4
DILAUDID
TABLETS
8 MILLIGRAM
TABLET
(C42998)
BOTTLE
(C43169)
100 TABLET
0074-
2426-14
DILAUDID ORAL LIQUID is a clear, sweet, slightly viscous liquid. It is available in: Bottles
of 1 pint (473 mL) - NDC# 0074-2452-02
DILAUDID 2 mg TABLETS are orange, debossed with the Abbott “A” logo on one side
and the number 2 on the opposite side. They are available in:
Bottles of 100 - NDC #0074-2415-14
Abbo-Pac® Unit Dose Packages of 100 (4x25) - NDC #0074-2415-12
DILAUDID 4 mg TABLETS are yellow, debossed with the Abbott “A” logo on one side
and the number 4 on the opposite side. They are available in:
Bottles of 100 - NDC #0074-2416-14.
Abbo-Pac® Unit Dose Packages of 100 (4x25) - NDC #0074-2416-12.
Bottles of 500 - NDC #0074-2416-54
DILAUDID 8 mg TABLETS are white and triangular shaped, debossed with a double
Abbott “A” logo on one side and bisected and debossed with the number 8 on the
opposite side. They are available in:
Bottles of 100 - NDC# 0074-2426-14
Storage
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled
Room Temperature]. Protect from light.
A schedule CS-II Narcotic. DEA Order Form is Required.
©Abbott
All rights reserved.
Abbott Laboratories, North Chicago, IL 60064, U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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|
custom-source
|
2025-02-12T13:46:14.960322
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019892s015lbl.pdf', 'application_number': 19892, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
11,823
|
1
PRAVACHOL®
(pravastatin sodium) Tablets
DESCRIPTION
PRAVACHOL® (pravastatin sodium) is one of a new class of lipid-lowering compounds,
the HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis. These agents
are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid,
1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula:
|
custom-source
|
2025-02-12T13:46:15.200484
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19898s50lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 50}
|
11,824
|
1
PRAVACHOL®
(pravastatin sodium) Tablets
DESCRIPTION
PRAVACHOL® (pravastatin sodium) is one of a new class of lipid-lowering compounds,
the HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis. These agents
are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid,
1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula:
C23 H35 NaO7 MW 446.52
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a
relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59
at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in
isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg
tablets. Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide,
magnesium stearate, microcrystalline cellulose, and povidone. The 10 mg tablet also
contains Red Ferric Oxide, the 20 mg and 80 mg tablets also contain Yellow Ferric
Oxide, and the 40 mg tablet also contains Green Lake Blend (mixture of D&C Yellow
No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
CLINICAL PHARMACOLOGY
Cholesterol and triglycerides in the bloodstream circulate as part of lipoprotein
complexes. These complexes can be separated by density ultracentrifugation into high
(HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein
fractions. Triglycerides (TG) and cholesterol synthesized in the liver are incorporated
into very low density lipoproteins (VLDLs) and released into the plasma for delivery to
peripheral tissues. In a series of subsequent steps, VLDLs are transformed into
intermediate density lipoproteins (IDLs), and cholesterol-rich low density lipoproteins
(LDLs). High density lipoproteins (HDLs), containing apolipoprotein A, are
hypothesized to participate in the reverse transport of cholesterol from tissues back to the
liver.
PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of
its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in
intracellular pools of cholesterol. This results in an increase in the number of LDL-
receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of
circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic
synthesis of VLDL, the LDL precursor.
Clinical and pathologic studies have shown that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B − a
membrane transport complex for LDL) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein
A, are associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with the level
of Total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-
enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also
promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low
HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic
risk factors for coronary heart disease. As such, total plasma TG has not consistently been
shown to be an independent risk factor for CHD. Furthermore, the independent effect of
raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and
mortality has not been determined. In both normal volunteers and patients with
hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and
apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases
in HDL-C and apolipoprotein A. The effects of pravastatin on Lp (a), fibrinogen, and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
certain other independent biochemical risk markers for coronary heart disease are
unknown. Although pravastatin is relatively more hydrophilic than other HMG-CoA
reductase inhibitors, the effect of relative hydrophilicity, if any, on either efficacy or
safety has not been established.
In one primary (West of Scotland Coronary Prevention Study - WOS)1 and two
secondary (Long-term Intervention with Pravastatin in Ischemic Disease - LIPID2 and the
Cholesterol and Recurrent Events - CARE3) prevention studies, PRAVACHOL has been
shown to reduce cardiovascular morbidity and mortality across a wide range of
cholesterol levels (see Clinical Studies).
Pharmacokinetics/Metabolism
PRAVACHOL (pravastatin sodium) is administered orally in the active form. In clinical
pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of
parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery
of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute
bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken
with, or 1 hour prior, to meals.
Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66),
which is its primary site of action, and the primary site of cholesterol synthesis and of
LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into
hepatocytes with substantially less uptake into other cells. In view of pravastatin’s
apparently extensive first-pass hepatic metabolism, plasma levels may not necessarily
correlate perfectly with lipid-lowering efficacy. Pravastatin plasma concentrations
[including: area under the concentration-time curve (AUC), peak (Cmax), and steady-state
minimum (Cmin)] are directly proportional to administered dose. Systemic bioavailability
of pravastatin administered following a bedtime dose was decreased 60% compared to
that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy
of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose. This finding of
lower systemic bioavailability suggests greater hepatic extraction of the drug following
the evening dose. Steady-state AUCs, Cmax and Cmin plasma concentrations showed no
evidence of pravastatin accumulation following once or twice daily administration of
PRAVACHOL (pravastatin sodium) tablets. Approximately 50% of the circulating drug
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
is bound to plasma proteins. Following single dose administration of 14C- pravastatin, the
elimination half-life (t½) for total radioactivity (pravastatin plus metabolites) in humans is
77 hours.
Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The
coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. Pravastatin 20 mg was administered under fasting conditions in adults. The
geometric means of Cmax and AUC ranged from 23.3 to 26.3 ng/mL and from 54.7 to
62.2 ng*hr/mL, respectively.
Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.
After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal
routes (i.e., biliary excretion and biotransformation). Since there are dual routes of
elimination, the potential exists both for compensatory excretion by the alternate route as
well as for accumulation of drug and/or metabolites in patients with renal or hepatic
insufficiency.
In a study comparing the kinetics of pravastatin in patients with biopsy confirmed
cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-
fold for cirrhotic patients compared to 6-fold for healthy subjects.
Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi
pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring
hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of
the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a
hydroxyl group to a keto group, and (g) conjugation. The major degradation product is
the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA
reductase inhibitory activity of the parent compound.
In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was
approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65 to 75 years old) compared with younger
men (19 to 31 years old). In a similar study conducted in women, the mean AUC for
pravastatin was approximately 46% higher and the mean CUE approximately 18% lower
in elderly women (65 to 78 years old) compared with younger women (18 to 38 years
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
old). In both studies, Cmax, Tmax and t½ values were similar in older and younger
subjects.
After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means
of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
n=14) and adolescents (12-16 years, n=10), respectively. The corresponding values for
Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents,
respectively. No conclusion can be made based on these findings due to the small
number of samples and large variability.
Clinical Studies
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (West of Scotland Coronary Prevention
Study – WOS)1, the effect of PRAVACHOL on fatal and nonfatal coronary heart disease
(CHD) was assessed in 6595 men 45–64 years of age, without a previous myocardial
infarction (MI), and with LDL-C levels between 156–254 mg/dL (4–6.7 mmol/L). In this
randomized, double-blind, placebo-controlled study, patients were treated with standard
care, including dietary advice, and either PRAVACHOL 40 mg daily (N=3302) or
placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th
percentile) percent changes from baseline after 6 months of pravastatin treatment in Total
C, LDL-C, TG, and HDL were –20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1 (-27.6,
12.5), and 6.7 (-2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either coronary
heart disease [CHD] death or nonfatal MI) by 31% [248 events in the placebo group
(CHD death=44, nonfatal MI=204) vs 174 events in the PRAVACHOL group (CHD
death=31, nonfatal MI=143), p=0.0001 (see figure below)]. The risk reduction with
PRAVACHOL was similar and significant throughout the entire range of baseline LDL
cholesterol levels. This reduction was also similar and significant across the age range
studied with a 40% risk reduction for patients younger than 55 years and a 27% risk
reduction for patients 55 years and older. The Pravastatin Primary Prevention Study
included only men and therefore it is not clear to what extent these data can be
extrapolated to a similar population of female patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
PRAVACHOL also significantly decreased the risk for undergoing myocardial
revascularization procedures (coronary artery bypass graft [CABG] surgery or
percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients,
p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths
were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)2 study, the
effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients (7498 men; 1516
women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina
pectoris (3260 patients) in the preceding 3-36 months. Patients in this multicenter,
double-blind, placebo-controlled study participated for an average of 5.6 years (median
of 5.9 years) and at randomization had total cholesterol between 114 and 563 mg/dL
(mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), triglycerides
between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL
(mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were
receiving antihypertensive medication. Treatment with PRAVACHOL significantly
reduced the risk for total mortality by reducing coronary death (see Table 1). The risk
reduction due to treatment with PRAVACHOL on CHD mortality was consistent
regardless of age. PRAVACHOL significantly reduced the risk for total mortality (by
reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who
qualified with a history of either MI or hospitalization for unstable angina pectoris.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 1:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N = 4512)
Placebo
(N = 4502)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or non-fatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the Cholesterol and Recurrent Events (CARE)3 study the effect of PRAVACHOL,
40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159
patients (3583 men and 576 women) who had experienced a myocardial infarction in the
preceding 3–20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo
controlled study participated for an average of 4.9 years and had a mean baseline total
cholesterol of 209 mg/dL. LDL cholesterol levels in this patient population ranged from
101 mg/dL–180 mg/dL (mean = 139 mg/dL). At baseline, 84% of patients were receiving
aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile)
percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C,
TG, and HDL were -22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1
(- 2.9, 12.7), respectively. Treatment with PRAVACHOL significantly reduced the rate
of first recurrent coronary events (either CHD death or nonfatal MI), the risk of
undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or
transient ischemic attack (TIA) (see Table 2).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Table 2:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N = 2081)
Placebo
(N = 2078)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality or non-fatal MI *
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
< 0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
*The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I)4
study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by
coronary
angiography
in
patients
with
coronary
disease
and
moderate
hypercholesterolemia (baseline LDL-C range = 130-190 mg/dL). In this double-blind,
multicenter, controlled clinical trial angiograms were evaluated at baseline and at three
years in 264 patients. Although the difference between pravastatin and placebo for the
primary endpoint (per-patient change in mean coronary artery diameter) and one of two
secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical
significance, for the secondary endpoint of change in minimum lumen diameter,
statistically significant slowing of disease was seen in the pravastatin treatment group
(p=0.02).
In the Regression Growth Evaluation Statin Study (REGRESS)5, the effect of pravastatin
on coronary atherosclerosis was assessed by coronary angiography in 885 patients with
angina
pectoris,
angiographically
documented
coronary
artery
disease
and
hypercholesterolemia (baseline total cholesterol range = 160-310 mg/dL). In this double-
blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at
two years in 653 patients (323 treated with pravastatin). Progression of coronary
atherosclerosis was significantly slowed in the pravastatin group as assessed by changes
in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, the Pravastatin, Lipids and Atherosclerosis in
the Carotids Study (PLAC II)6, REGRESS, and the Kuopio Atherosclerosis Prevention
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Study (KAPS)7 (combined N=1891) showed that treatment with pravastatin was
associated with a statistically significant reduction in the composite event rate of fatal and
nonfatal myocardial infarction (46 events or 6.4% for placebo versus 21 events or 2.4%
for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of
nonfatal myocardial infarction.
Primary Hypercholesterolemia (Fredrickson Type IIa and IIb)
PRAVACHOL (pravastatin sodium) is highly effective in reducing Total-C, LDL-C and
Triglycerides (TG) in patients with heterozygous familial, presumed familial combined
and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed
dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response
usually is achieved within 4 weeks. This response is maintained during extended periods
of therapy. In addition, PRAVACHOL is effective in reducing the risk of acute coronary
events in hypercholesterolemic patients with and without previous myocardial infarction.
A single daily dose is as effective as the same total daily dose given twice a day. In
multicenter, double-blind, placebo-controlled studies of patients with primary
hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 mg to
40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C
and LDL-C/HDL-C ratios (see Table 3).
In a pooled analysis of two multicenter, double-blind, placebo-controlled studies of
patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of
80 mg (N = 277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th
percentile changes from baseline in LDL-C for pravastatin 80 mg were -43% and -30%.
The efficacy results of the individual studies were consistent with the pooled data (see
Table 3).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across
all doses produced variable increases in HDL-C (see Table 3).
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Table 3:
Primary Hypercholesterolemia Studies:
Dose Response of PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeks*
Placebo (N = 36)
-3%
-4%
+1%
-4%
10 mg (N = 18)
-16%
-22%
+7%
-15%
20 mg (N = 19)
-24%
-32%
+2%
-11%
40 mg (N = 18)
-25%
-34%
+12%
-24%
Mean Percent Changes From Baseline After 6 Weeks**
Placebo (N = 162 )
0%
-1%
-1%
+1%
80 mg (N = 277)
-27%
-37%
+3%
-19%
* a multicenter, double-blind, placebo-controlled study
** pooled analysis of 2 multicenter, double-blind, placebo-controlled studies
In another clinical trial, patients treated with pravastatin in combination with
cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had
reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated
cholestyramine-induced increases in TG levels (which are themselves of uncertain
clinical significance).
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200
mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the
Cholesterol and Recurrent Events (CARE) study. For pravastatin-treated subjects, the
median (min, max) baseline triglyceride level was 246.0 (200.5, 349.5) mg/dL. (See
Table 4).
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Table 4:
Patients With Fredrickson Type IV Hyperlipidemia
Median (25th, 75th percentile) Percent Change From Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
Triglycerides
-21.1 (-34.8, 1.3)
-6.3 (-23.1, 18.3)
Total-C
-22.1 (-27.1, -14.8)
0.2 (-6.9, 6.8)
LDL-C
-31.7 (-39.6, -21.5)
0.7 (-9.0, 10.0)
HDL-C
7.4 (-1.2, 17.7)
2.8 (-5.7, 11.7)
Non-HDL-C
-27.2 (-34.0, -18.5)
-0.8 (-8.2, 7.0)
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with
genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 5.
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Table 5:
Patients With Fredrickson Type III Dysbetalipoproteinemia
Median (min, max) Percent Change From Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
-32.7 (-58.5, 4.6)
Triglycerides
443.0 (275.0, 1299.0)
-23.7 (-68.5, 44.7)
VLDL-C *
206.5 (110.0, 379.0)
-43.8 (-73.1, -14.3)
LDL-C *
117.5 (80.0, 170.0)
-40.8 (-63.7, 4.6)
HDL-C
30.0 (18.0, 88.0)
6.4 (-45.0, 105.6)
Non-HDL-C
* N=14
344.5 (215.0, 646.0)
-36.7 (-66.3, 5.8)
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
-31.4 (-54.5, -13.0)
Triglycerides
343.2 (212.6, 845.9)
-11.9 (-56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
-35.7 (-74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
-30.3 (-52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (-17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
-35.5 (-81.0, -13.5)
Pediatric Clinical Study
A double-blind placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8-18 years was conducted for
two (2) years. The children (aged 8-13 years) were randomized to placebo (n=63) or
20 mg of pravastatin daily (n=65) and the adolescents (aged 14-18 years) were
randomized to placebo (n=45) or 40 mg of pravastatin daily (n=41). Inclusion in the
study required an LDL-C level > 95th percentile for age and sex and one parent with
either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean
baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151-405
mg/dL) and placebo (range: 154-375 mg/dL) groups, respectively.
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Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and apolipoprotein
B in both children and adolescents (see Table 6). The effect of pravastatin treatment in
the two age groups was similar.
Table 6:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients
with Heterozygous Familial Hypercholesterolemia:Least-
Squares Mean Percent Change from Baseline at Month 24
(Last Observation Carried Forward: Intent-to-Treat)*
Pravastatin
20-mg
(Aged 8-13
years)
N = 65
Pravastatin
40-mg
(Aged 14-18
years)
N = 41
Combined
Pravastatin
(Aged 8-18
years)
N = 106
Combined
Placebo
(Aged 8-18
years)
N = 108
95% CI of the
difference
between
combined
pravastatin and
placebo
LDL-C
-26.04**
-21.07 **
-24.07 **
-1.52
(-26.74, -18.86)
TC
-20.75**
-13.08**
-17.72 **
-0.65
(-20.40, -13.83)
HDL-C
1.04
13.71
5.97
3.13
(-1.71, 7.43)
TG
-9.58
-0.30
-5.88
-3.27
(-13.95, 10.01)
ApoB
(N)
-23.16**
(61)
-18.08**
(39)
-21.11**
(100)
-0.97
(106)
(-24.29, -16.18)
* The above least-squares mean values were calculated based on log-transformed lipid values.
** Significant at p ≤ 0.0001 when compared with placebo
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin
group compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in
children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity
and mortality in adulthood has not been established.
INDICATIONS AND USAGE
Therapy with PRAVACHOL (pravastatin sodium) should be considered in those
individuals at increased risk for atherosclerosis-related clinical events as a function of
cholesterol level, the presence or absence of coronary heart disease, and other risk
factors.
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Primary Prevention of Coronary Events
In hypercholesterolemic patients without clinically evident coronary heart disease,
PRAVACHOL (pravastatin sodium) is indicated to:
• Reduce the risk of myocardial infarction
• Reduce the risk of undergoing myocardial revascularization procedures
•
Reduce the risk of cardiovascular mortality with no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In patients with clinically evident coronary heart disease, PRAVACHOL (pravastatin
sodium) is indicated to:
• Reduce the risk of total mortality by reducing coronary death
• Reduce the risk of myocardial infarction
• Reduce the risk of undergoing myocardial revascularization procedures
• Reduce the risk of stroke and stroke/transient ischemic attack (TIA)
• Slow the progression of coronary atherosclerosis.
Hyperlipidemia
PRAVACHOL is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, Apo
B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia
and mixed dyslipidemia (Frederickson Type IIa and IIb)8.
PRAVACHOL is indicated as adjunctive therapy to diet for the treatment of patients with
elevated serum triglyceride levels (Fredrickson Type IV).
PRAVACHOL
is
indicated
for
the
treatment
of
patients
with
primary
dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
PRAVACHOL is indicated as an adjunct to diet and lifestyle modification for treatment
of HeFH in children and adolescent patients ages 8 years and older if after an adequate
trial of diet the following findings are present:
1. LDL-C remains ≥ 190 mg/dL or
2. LDL-C remains ≥ 160 mg/dL and:
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• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the patient
Lipid-altering agents should be used in addition to a diet restricted in saturated fat and
cholesterol when the response to diet and other nonpharmacological measures alone has
been inadequate (see NCEP Guidelines below).
Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia
(e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome,
dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be
excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients
with triglycerides (TG) <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the
following equation:
LDL-C = Total -C - HDL-C – 1/5 TG
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C
concentrations
should
be
determined
by
ultracentrifugation.
In
many
hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In
such cases, HMG-CoA reductase inhibitors are not indicated.
Lipid determinations should be performed at intervals of no less than four weeks and
dosage adjusted according to the patient’s response to therapy.
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The National Cholesterol Education Program’s Treatment Guidelines are summarized
below:
NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic
Lifestyle Changes and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHDa or CHD risk
equivalents
(10-year risk > 20%)
< 100
≥ 100
≥ 130
(100-129: drug optional)b
10-year risk 10%-20%: ≥ 130
2+ Risk factors
(10-year risk ≤ 20 %)
< 130
≥ 130
10-year risk < 10%: ≥ 160
0 -1 Risk factorc
< 160
≥ 160
≥ 190
(160-189: LDL-lowering
drug optional)
a CHD, coronary heart disease.
b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of
<100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that
primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may
call for deferring drug therapy in this subcategory.
c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people
with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, non-HDL-C
(Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are
set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to
initiating drug therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Guidelines,
above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels
be used to initiate and assess treatment response. Only if LDL-C levels are not available,
should the Total-C be used to monitor therapy.
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As with other lipid-lowering therapy, PRAVACHOL (pravastatin sodium) is not
indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated
HDL-C).
The NCEP classification of cholesterol levels in pediatric patients with a familial history
of hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations in liver function tests (see
WARNINGS).
Pregnancy and Lactation. Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome of long-
term therapy of primary hypercholesterolemia. Cholesterol and other products of
cholesterol biosynthesis are essential components for fetal development (including
synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors
decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in
nursing mothers. Pravastatin should be administered to women of childbearing age
only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. If the patient becomes pregnant while taking this class of drug,
therapy should be discontinued immediately and the patient apprised of the potential
hazard to the fetus (see PRECAUTIONS: Pregnancy).
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WARNINGS
Liver Enzymes
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been
associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9
years), placebo-controlled clinical trials (WOS, LIPID, CARE; see CLINICAL
PHARMACOLOGY: Clinical Studies), 19,592 subjects (19,768 randomized), were
exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT,
AST), incidences of marked abnormalities were compared between the pravastatin and
placebo treatment groups; a marked abnormality was defined as a post-treatment test
value greater than three times the upper limit of normal for subjects with pretreatment
values less than or equal to the upper limit of normal, or four times the pretreatment value
for subjects with pretreatment values greater than the upper limit of normal but less than
1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with
similar low frequency (≤ 1.2%) in both treatment groups. Overall, clinical trial
experience showed that liver function test abnormalities observed during pravastatin
therapy were usually asymptomatic, not associated with cholestasis, and did not appear to
be related to treatment duration.
It is recommended that liver function tests be performed prior to the initiation of
therapy, prior to the elevation of the dose, and when otherwise clinically indicated.
Active
liver
disease
or
unexplained
persistent
transaminase
elevations
are
contraindications to the use of pravastatin (see CONTRAINDICATIONS). Caution
should be exercised when pravastatin is administered to patients who have a recent
history of liver disease, have signs that may suggest liver disease (e.g., unexplained
aminotransferase elevations, jaundice), or are heavy users of alcohol (see CLINICAL
PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely
monitored, started at the lower end of the recommended dosing range, and titrated to the
desired therapeutic effect.
Patients who develop increased transaminase levels or signs and symptoms of liver
disease should be monitored with a second liver function evaluation to confirm the
finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) return to normal. Should an increase in AST or ALT of three times the
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upper limit of normal or greater persist, withdrawal of pravastatin therapy is
recommended.
Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria
have been reported with pravastatin and other drugs in this class. Uncomplicated
myalgia has also been reported in pravastatin-treated patients (see ADVERSE
REACTIONS). Myopathy, defined as muscle aching or muscle weakness in conjunction
with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper
normal limit, was rare (<0.1%) in pravastatin clinical trials. Myopathy should be
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or
marked elevation of CPK. Patients should be advised to report promptly unexplained
muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Pravastatin therapy should be discontinued if markedly elevated CPK levels occur
or myopathy is diagnosed or suspected. Pravastatin therapy should also be
temporarily withheld in any patient experiencing an acute or serious condition
predisposing to the development of renal failure secondary to rhabdomyolysis, e.g.,
sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or
electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is
increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or
fibrates. However, neither myopathy nor significant increases in CPK levels have been
observed in three reports involving a total of 100 post-transplant patients (24 renal and 76
cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and
cyclosporine. Some of these patients also received other concomitant immunosuppressive
therapies. Further, in clinical trials involving small numbers of patients who were treated
concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and
gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked
CPK elevations versus one of 73 patients receiving placebo. There was a trend toward
more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms
in the group receiving combined treatment as compared with the groups receiving
placebo, gemfibrozil, or pravastatin monotherapy (see PRECAUTIONS: Drug
Interactions). The use of fibrates alone may occasionally be associated with
myopathy. The combined use of pravastatin and fibrates should be avoided unless
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the benefit of further alterations in lipid levels is likely to outweigh the increased
risk of this drug combination.
PRECAUTIONS
General
PRAVACHOL (pravastatin sodium) may elevate creatine phosphokinase and
transaminase levels (see ADVERSE REACTIONS). This should be considered in the
differential diagnosis of chest pain in a patient on therapy with pravastatin.
Homozygous Familial Hypercholesterolemia
Pravastatin has not been evaluated in patients with rare homozygous familial
hypercholesterolemia. In this group of patients, it has been reported that HMG-CoA
reductase inhibitors are less effective because the patients lack functional LDL receptors.
Renal Insufficiency
A single 20 mg oral dose of pravastatin was administered to 24 patients with varying
degrees of renal impairment (as determined by creatinine clearance). No effect was
observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite
(SQ 31,906). A small increase was seen in mean AUC values and half-life (t½) for the
inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Given this small sample
size, the dosage administered, and the degree of individual variability, patients with renal
impairment who are receiving pravastatin should be closely monitored.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever (see WARNINGS: Skeletal
Muscle).
Drug Interactions
Immunosuppressive
Drugs,
Gemfibrozil,
Niacin
(Nicotinic
Acid),
Erythromycin: See WARNINGS: Skeletal Muscle.
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Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is
not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been
shown in studies with known cytochrome P450 3A4 inhibitors (see diltiazem and
itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include
ketoconazole, mibefradil, and erythromycin.
Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had
no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of
another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome
P450 3A4 increased by factors of 3.6 and 4.3, respectively.
Itraconazole: The mean AUC and Cmax for pravastatin were increased by factors of 1.7
and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which
also inhibits p-glycoprotein transport) as compared to placebo. The mean t½ was not
affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC
were due solely to increased bioavailability rather than a decrease in clearance, consistent
with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is
thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors,
including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19
and 17, respectively, when given with itraconazole.
Antipyrine: Since concomitant administration of pravastatin had no effect on the
clearance of antipyrine, interactions with other drugs metabolized via the same hepatic
cytochrome isozymes are not expected.
Cholestyramine/Colestipol: Concomitant administration resulted in an approximately
40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was
administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol
and a standard meal, there was no clinically significant decrease in bioavailability or
therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant
Therapy.)
Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant
effect on prothrombin time when administered in a study to normal elderly subjects who
were stabilized on warfarin.
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Cimetidine: The AUC0-12hr for pravastatin when given with cimetidine was not
significantly different from the AUC for pravastatin when given alone. A significant
difference was observed between the AUC’s for pravastatin when given with cimetidine
compared to when administered with antacid.
Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin
and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin
were not affected. The AUC of pravastatin tended to increase, but the overall
bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not
altered.
Cyclosporine: Some investigators have measured cyclosporine levels in patients on
pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful
elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found
to be increased in cardiac transplant patients receiving cyclosporine.
Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant
single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary
excretion and protein binding of pravastatin. In addition, there was a significant increase
in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906. Combination therapy
with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS:
Skeletal Muscle.)
In interaction studies with aspirin, antacids (1 hour prior to PRAVACHOL), cimetidine,
nicotinic acid, or probucol, no statistically significant differences in bioavailability were
seen when PRAVACHOL (pravastatin sodium) was administered.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating
cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid
hormone production. Results of clinical trials with pravastatin in males and post-
menopausal females were inconsistent with regard to possible effects of the drug on basal
steroid hormone levels. In a study of 21 males, the mean testosterone response to human
chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment
with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change
significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors
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23
on spermatogenesis and fertility have not been studied in adequate numbers of patients.
The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females
are unknown. Patients treated with pravastatin who display clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may diminish the levels or activity of steroid hormones.
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were
treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the
adolescents aged 14-18 years) for two years, there were no detectable differences seen in
any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol
(girls) or testosterone (boys)] relative to placebo. There were no detectable differences
seen in height and weight changes, testicular volume changes, or Tanner score relative to
placebo.
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and
mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with
pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at
approximately 59 times the human dose of 80 mg/day, based on AUC. Similar CNS
vascular lesions have been observed with several other drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30
times higher than the mean drug level in humans taking the highest recommended dose
(as measured by total enzyme inhibitory activity). This same drug also produced
vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in
dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug
level similar to that seen with the 60 mg/kg/day dose.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight,
there was an increased incidence of hepatocellular carcinomas in males at the highest
dose (p <0.01). These effects in rats were observed at approximately 12 times the human
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24
dose (HD) of 80 mg based on body surface area mg/m2 and at approximately 4 times the
human dose, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased
(p=0.013). These effects in mice were observed at approximately 15 times (250
mg/kg/day) and 23 times (500 mg/kg/day) the human dose of 80 mg, based on AUC. In
another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures
approximately 2 times the human dose of 80 mg, based on AUC), there were no drug-
induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of
Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/-
mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene
conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of
mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.
In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance. However, in a study with
another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated
for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a
subsequent fertility study when this same dose was administered for 11 weeks (the entire
cycle of spermatogenesis, including epididymal maturation). In rats treated with this
same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis
and loss of spermatogenic epithelium) was observed. Although not seen with pravastatin,
two similar drugs in this class caused drug-related testicular atrophy, decreased
spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The
clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X.
See CONTRAINDICATIONS.
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25
Safety in pregnant women has not been established. Pravastatin was not teratogenic in
rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These
doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area
(mg/meter2). Rare reports of congenital anomalies have been received following
intrauterine exposure to other HMG-CoA reductase inhibitors. In a review9 of
approximately 100 prospectively followed pregnancies in women exposed to simvastatin
or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal
deaths/stillbirths did not exceed what would be expected in the general population. The
number of cases is adequate only to exclude a three-to-four-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at
some point in the first trimester when pregnancy was identified. As safety in pregnant
women has not been established and there is no apparent benefit to therapy with
PRAVACHOL during pregnancy (see CONTRAINDICATIONS), treatment should be
immediately discontinued as soon as pregnancy is recognized. PRAVACHOL
(pravastatin sodium) should be administered to women of child-bearing potential only
when such patients are highly unlikely to conceive and have been informed of the
potential hazards.
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential
for serious adverse reactions in nursing infants, women taking PRAVACHOL should not
nurse (see CONTRAINDICATIONS).
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8-18
years of age have been evaluated in a placebo-controlled study of 2 years duration.
Patients treated with pravastatin had an adverse experience profile generally similar to
that of patients treated with placebo with influenza and headache commonly reported in
both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses
greater than 40 mg have not been studied in this population. Children and adolescent
females of childbearing potential should be counseled on appropriate contraceptive
methods
while
on
pravastatin
therapy
(see
CONTRAINDICATIONS
and
PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND
ADMINISTRATION: Adult Patients and Pediatric Patients.
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26
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age
have not been conducted.
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of
6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across
these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were
aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing
cardiovascular events and in modifying lipid profiles was similar to that seen in younger
subjects. The adverse event profile in the elderly was similar to that in the overall
population. Other reported clinical experience has not identified differences in responses
to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy
young subjects, but mean Cmax, Tmax and t1/2 values are similar in both age groups and
substantial accumulation of pravastatin would not be expected in the elderly (see
CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism).
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and
transient. In 4-month long placebo-controlled trials, 1.7% of pravastatin-treated patients
and 1.2% of placebo-treated patients were discontinued from treatment because of
adverse experiences attributed to study drug therapy; this difference was not statistically
significant. (See also PRECAUTIONS: Geriatric Use section.)
Adverse Clinical Events
Short-Term Controlled Trials
All adverse clinical events (regardless of attribution) reported in more than 2% of
pravastatin-treated patients in placebo-controlled trials of up to four months duration are
identified in Table 7; also shown are the percentages of patients in whom these medical
events were believed to be related or possibly related to the drug:
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27
Table 7:
Adverse Events in > 2 Percent of Patients Treated with
Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials
All Events
Events Attributed
to Study Drug
Body System/Event
Pravastatin
(N = 900)
% of patients
Placebo
(N = 411)
% of patients
Pravastatin
(N = 900)
% of patients
Placebo
(N = 411)
% of patients
Cardiovascular
Cardiac Chest Pain
4.0
3.4
0.1
0.0
Dermatologic
Rash
4.0*
1.1
1.3
0.9
Gastrointestinal
Nausea/Vomiting
Diarrhea
Abdominal Pain
Constipation
Flatulence
Heartburn
7.3
6.2
5.4
4.0
3.3
2.9
7.1
5.6
6.9
7.1
3.6
1.9
2.9
2.0
2.0
2.4
2.7
2.0
3.4
1.9
3.9
5.1
3.4
0.7
General
Fatigue
Chest Pain
Influenza
3.8
3.7
2.4*
3.4
1.9
0.7
1.9
0.3
0.0
1.0
0.2
0.0
Musculoskeletal
Localized Pain
Myalgia
10.0
2.7
9.0
1.0
1.4
0.6
1.5
0.0
Nervous System
Headache
Dizziness
6.2
3.3
3.9
3.2
1.7*
1.0
0.2
0.5
Renal/ Genitourinary
Urinary Abnormality
2.4
2.9
0.7
1.2
Respiratory
Common Cold
Rhinitis
Cough
7.0
4.0
2.6
6.3
4.1
1.7
0.0
0.1
0.1
0.0
0.0
0.0
*Statistically significantly different from placebo.
The safety and tolerability of PRAVACHOL at a dose of 80 mg in two controlled trials
with a mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses
except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of
CK > 10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.
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Long-Term Controlled Morbidity and Mortality Trials
Adverse event data were pooled from seven double-blind, placebo-controlled trials (West
of Scotland Coronary Prevention study [WOS]; Cholesterol and Recurrent Events study
[CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID];
Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I];
Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression
Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention
Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and
10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin
group was comparable to that of the placebo group. Patients were exposed to pravastatin
for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I,
PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for
discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these
seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to
be of probable, possible, or uncertain relationship to study drug, occurring in at least 1%
of patients treated with pravastatin in these studies are identified in Table 8.
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Table 8: Adverse Events in ≥ 1 Percent of Patients Treated with Pravastatin
40 mg in Long-Term Placebo-Controlled Trials
Body System/Event
Pravastatin
(N = 10,764)
% of patients
Placebo
(N = 10,719)
% of patients
Cardiovascular
Angina Pectoris
3.1
3.4
Dermatologic
Rash
2.1
2.2
Gastrointestinal
Dyspepsia/Heartburn
Abdominal Pain
Nausea/Vomiting
Flatulence
Constipation
3.5
2.4
1.6
1.2
1.2
3.7
2.5
1.6
1.1
1.3
General
Fatigue
Chest Pain
3.4
2.6
3.3
2.6
Musculoskeletal
Musculoskeletal Pain (includes arthralgia)
Muscle Cramp
Myalgia
6.0
2.0
1.4
5.8
1.8
1.4
Nervous System
Dizziness
Headache
Sleep Disturbance
Depression
Anxiety/Nervousness
2.2
1.9
1.0
1.0
1.0
2.1
1.8
0.9
1.0
1.2
Renal/Genitourinary
Urinary Abnormality (includes dysuria, frequency, nocturia)
1.0
0.8
Respiratory
Dyspnea
Upper Respiratory Infection
Cough
1.6
1.3
1.0
1.6
1.3
1.0
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
1.6
1.3
Events of probable, possible, or uncertain relationship to study drug that occurred in
<1.0% of pravastatin-treated patients in the long-term trials included the following;
frequencies were similar in placebo-treated patients:
Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including
alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
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30
Gastrointestinal: decreased appetite.
General: fever, flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy
(including peripheral neuropathy).
Special Senses: lens opacity, taste disturbance.
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following
events have been reported rarely during postmarketing experience with PRAVACHOL,
regardless of causality assessment:
Musculoskeletal: myopathy, rhabdomyolysis.
Nervous System: dysfunction of certain cranial nerves (including alteration of taste,
impairment of extra-ocular movement, facial paresis), peripheral nerve palsy.
Hypersensitivity: anaphylaxis, lupus erythematosus-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR
increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal
necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic
jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma.
Dermatologic: A variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Reproductive: gynecomastia.
Laboratory Abnormalities: elevated alkaline phosphatase and bilirubin; thyroid function
abnormalities.
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31
Laboratory Test Abnormalities
Increases in serum transaminase (ALT, AST) values and CPK have been observed (see
WARNINGS).
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually
returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia
have been reported with HMG-CoA reductase inhibitors.
Concomitant Therapy
Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic
acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either
probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with
greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin
alone. No adverse reactions unique to the combination or in addition to those previously
reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or
without acute renal failure) have been reported when another HMG-CoA reductase
inhibitor was used in combination with immunosuppressive drugs, gemfibrozil,
erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-
CoA reductase inhibitors and these agents is generally not recommended. (See
WARNINGS: Skeletal Muscle and PRECAUTIONS: Drug Interactions.)
Pediatric Patients
In a two (2) year double-blind placebo-controlled study involving 100 boys and 114 girls
with HeFH, the safety and tolerability profile of pravastatin was generally similar to that
of placebo. (See CLINICAL PHARMACOLOGY, Pediatric Clinical Study and
PRECAUTIONS, Pediatric Use.)
OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose
occurs, it should be treated symptomatically with laboratory monitoring and supportive
measures should be instituted as required. (See WARNINGS.)
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32
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL (pravastatin sodium) and should continue on this diet during treatment
with PRAVACHOL (see NCEP Treatment Guidelines for details on dietary therapy).
PRAVACHOL can be administered orally as a single dose at any time of the day, with or
without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic
lipid determinations should be performed at this time and dosage adjusted according to
the patient’s response to therapy and established treatment guidelines.
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not
achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a
history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is
recommended.
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses
greater than 20 mg have not been studied in this patient population.
Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age.
Doses greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be re-evaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C (see INDICATIONS AND USAGE, Hyperlipidemia, NCEP Treatment
Guidelines).
In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS:
Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of
pravastatin once-a-day at bedtime and titration to higher doses should be done with
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33
caution. Most patients treated with this combination received a maximum pravastatin
dose of 20 mg/day.
Concomitant Therapy
The lipid-lowering effects of PRAVACHOL on total and LDL cholesterol are enhanced
when combined with a bile-acid-binding resin. When administering a bile-acid-binding
resin (e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given
either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE
REACTIONS: Concomitant Therapy.)
HOW SUPPLIED
PRAVACHOL® (pravastatin sodium) Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a P embossed
on one side and PRAVACHOL 10 engraved on the opposite side. They are supplied in
bottles of 90 (NDC 0003-5154-05). Bottles contain a desiccant canister.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a P embossed on one
side and PRAVACHOL 20 engraved on the opposite side. They are supplied in bottles of
90 (NDC 0003-5178-05) and bottles of 1000 (NDC 0003-5178-75). Bottles contain a
desiccant canister.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a P embossed on one
side and PRAVACHOL 40 engraved on the opposite side. They are supplied in bottles of
90 (NDC 0003-5194-10). Bottles contain a desiccant canister.
80 mg tablets: Yellow, oval-shaped, biconvex with BMS embossed on one side and 80
engraved on the opposite side. They are supplied in bottles of 90 (NDC 0003-5195-10)
and bottles of 500 (NDC 0003-5195-12). Bottles contain a desiccant canister.
Unimatic® unit-dose packs containing 100 tablets are also available for the 20 mg (NDC
0003-5178-06) potency.
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34
STORAGE
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP
Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect
from light.
REFERENCES
1 Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in Men with
Hypercholesterolemia (WOS). N Engl J Med 1995; 333:1301–7.
2 The Long-term Intervention with Pravastatin in Ischemic Disease Group. Prevention of
Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart
Disease and a Broad Range of Initial Cholesterol Levels (LIPID). N Engl J Med
1998; 339:1349-1357.
3 Sacks FM, et al. The Effect of Pravastatin on Coronary Events After Myocardial
Infarction in Patients with Average Cholesterol Levels (CARE). N Engl J Med 1996;
335:1001-9.
4 Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC
I): Reduction in Atherosclerosis Progression and Clinical Events. J Am Coll Cardiol
1995; 26:1133-9.
5 Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression and
Regression of Coronary Artery Disease in Symptomatic Man with Normal to
Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation
Statin Study (REGRESS). Circulation 1995; 91:2528–2540.
6 Crouse JR, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries: Design
Features of a Clinical Trial with Carotid Atherosclerosis Outcome (PLAC II).
Controlled Clinical Trials 1992; 13:495.
7 Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A Population-based
Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic
Progression in Carotid and Femoral Arteries. Research Institute of Public Health,
University of Kuopio, Finland. Circulation 1995; 92:1758.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
8 Fredrickson DS, et al. Fat Transport in Lipoproteins-An Integrated Approach to
Mechanisms and Disorders. N Engl J Med 1967; 276:34-42, 94-102, 148-156, 215-
224, 273-281.
9 Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing Surveillance
of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology
1996; 10(6):439-446.
US Patent Nos.: 4,346,227; 5,030,447; 5,180,589; 5,622,985
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
5154DIM-21
515432DIM-12
Revised March 2003
J4-538U
1109268A9
1092990B2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:15.251026
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19898slr054_pravachol_lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 54}
|
11,825
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1
PRAVACHOL®
(pravastatin sodium) Tablets
DESCRIPTION
PRAVACHOL® (pravastatin sodium) is one of a class of lipid-lowering compounds, the
HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis. These agents are
competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid,
1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula:
C23 H35 NaO7 MW 446.52
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a
relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59
at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in
isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg
tablets. Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide,
magnesium stearate, microcrystalline cellulose, and povidone. The 10 mg tablet also
contains Red Ferric Oxide, the 20 mg and 80 mg tablets also contain Yellow Ferric
Oxide, and the 40 mg tablet also contains Green Lake Blend (mixture of D&C Yellow
No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).
Rx only
Bristol-Myers Squibb Company
Approved 1.0
current.pdf Page 001
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2
CLINICAL PHARMACOLOGY
Cholesterol and triglycerides in the bloodstream circulate as part of lipoprotein
complexes. These complexes can be separated by density ultracentrifugation into high
(HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein
fractions. Triglycerides (TG) and cholesterol synthesized in the liver are incorporated into
very low density lipoproteins (VLDLs) and released into the plasma for delivery to
peripheral tissues. In a series of subsequent steps, VLDLs are transformed into
intermediate density lipoproteins (IDLs), and cholesterol-rich low density lipoproteins
(LDLs). High density lipoproteins (HDLs), containing apolipoprotein A, are
hypothesized to participate in the reverse transport of cholesterol from tissues back to the
liver.
PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of
its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in
intracellular pools of cholesterol. This results in an increase in the number of LDL-
receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of
circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic
synthesis of VLDL, the LDL precursor.
Clinical and pathologic studies have shown that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B − a
membrane transport complex for LDL) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein
A, are associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with the level
of Total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-
enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also
promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low
HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic
risk factors for coronary heart disease. As such, total plasma TG has not consistently been
shown to be an independent risk factor for CHD. Furthermore, the independent effect of
raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and
mortality has not been determined. In both normal volunteers and patients with
hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and
apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases
in HDL-C and apolipoprotein A. The effects of pravastatin on Lp (a), fibrinogen, and
certain other independent biochemical risk markers for coronary heart disease are
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unknown. Although pravastatin is relatively more hydrophilic than other HMG-CoA
reductase inhibitors, the effect of relative hydrophilicity, if any, on either efficacy or
safety has not been established.
In one primary (West of Scotland Coronary Prevention Study - WOS)1 and two
secondary (Long-term Intervention with Pravastatin in Ischemic Disease - LIPID2 and the
Cholesterol and Recurrent Events - CARE3) prevention studies, PRAVACHOL has been
shown to reduce cardiovascular morbidity and mortality across a wide range of
cholesterol levels (see Clinical Studies).
Pharmacokinetics/Metabolism
PRAVACHOL (pravastatin sodium) is administered orally in the active form. In clinical
pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of
parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery
of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute
bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken
with, or 1 hour prior, to meals.
Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66),
which is its primary site of action, and the primary site of cholesterol synthesis and of
LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into
hepatocytes with substantially less uptake into other cells. In view of pravastatin’s
apparently extensive first-pass hepatic metabolism, plasma levels may not necessarily
correlate perfectly with lipid-lowering efficacy. Pravastatin plasma concentrations
[including: area under the concentration-time curve (AUC), peak (Cmax), and steady-state
minimum (Cmin)] are directly proportional to administered dose. Systemic bioavailability
of pravastatin administered following a bedtime dose was decreased 60% compared to
that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy
of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose. This finding of
lower systemic bioavailability suggests greater hepatic extraction of the drug following
the evening dose. Steady-state AUCs, Cmax and Cmin plasma concentrations showed no
evidence of pravastatin accumulation following once or twice daily administration of
PRAVACHOL (pravastatin sodium) tablets. Approximately 50% of the circulating drug
is bound to plasma proteins. Following single dose administration of 14C-pravastatin, the
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elimination half-life (t½) for total radioactivity (pravastatin plus metabolites) in humans is
77 hours.
Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The
coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. Pravastatin 20 mg was administered under fasting conditions in adults. The
geometric means of Cmax and AUC ranged from 23.3 to 26.3 ng/mL and from 54.7 to
62.2 ng*hr/mL, respectively.
Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.
After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal
routes (i.e., biliary excretion and biotransformation). Since there are dual routes of
elimination, the potential exists both for compensatory excretion by the alternate route as
well as for accumulation of drug and/or metabolites in patients with renal or hepatic
insufficiency.
In a study comparing the kinetics of pravastatin in patients with biopsy confirmed
cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied
47-fold for cirrhotic patients compared to 6-fold for healthy subjects.
Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi
pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring
hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of
the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a
hydroxyl group to a keto group, and (g) conjugation. The major degradation product is
the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA
reductase inhibitory activity of the parent compound.
In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was
approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65 to 75 years old) compared with younger
men (19 to 31 years old). In a similar study conducted in women, the mean AUC for
pravastatin was approximately 46% higher and the mean CUE approximately 18% lower
in elderly women (65 to 78 years old) compared with younger women (18 to 38 years
old). In both studies, Cmax, Tmax and t½ values were similar in older and younger subjects.
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After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means
of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
n=14) and adolescents (12-16 years, n=10), respectively. The corresponding values for
Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents,
respectively. No conclusion can be made based on these findings due to the small number
of samples and large variability.
Clinical Studies
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (West of Scotland Coronary Prevention
Study – WOS)1, the effect of PRAVACHOL on fatal and nonfatal coronary heart disease
(CHD) was assessed in 6595 men 45–64 years of age, without a previous myocardial
infarction (MI), and with LDL-C levels between 156–254 mg/dL (4–6.7 mmol/L). In this
randomized, double-blind, placebo-controlled study, patients were treated with standard
care, including dietary advice, and either PRAVACHOL 40 mg daily (N=3302) or
placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th
percentile) percent changes from baseline after 6 months of pravastatin treatment in
Total C, LDL-C, TG, and HDL were -20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1 (-27.6,
12.5), and 6.7 (-2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either coronary
heart disease [CHD] death or nonfatal MI) by 31% [248 events in the placebo group
(CHD death=44, nonfatal MI=204) vs 174 events in the PRAVACHOL group (CHD
death=31, nonfatal MI=143), p=0.0001 (see figure below)]. The risk reduction with
PRAVACHOL was similar and significant throughout the entire range of baseline LDL
cholesterol levels. This reduction was also similar and significant across the age range
studied with a 40% risk reduction for patients younger than 55 years and a 27% risk
reduction for patients 55 years and older. The Pravastatin Primary Prevention Study
included only men and therefore it is not clear to what extent these data can be
extrapolated to a similar population of female patients.
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PRAVACHOL also significantly decreased the risk for undergoing myocardial
revascularization procedures (coronary artery bypass graft [CABG] surgery or
percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients,
p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths
were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)2 study, the
effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients (7498 men; 1516
women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina
pectoris (3260 patients) in the preceding 3-36 months. Patients in this multicenter,
double-blind, placebo-controlled study participated for an average of 5.6 years (median
of 5.9 years) and at randomization had total cholesterol between 114 and 563 mg/dL
(mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), triglycerides
between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL
(mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were
receiving antihypertensive medication. Treatment with PRAVACHOL significantly
reduced the risk for total mortality by reducing coronary death (see Table 1). The risk
reduction due to treatment with PRAVACHOL on CHD mortality was consistent
regardless of age. PRAVACHOL significantly reduced the risk for total mortality (by
reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who
qualified with a history of either MI or hospitalization for unstable angina pectoris.
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Table 1:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N = 4512)
Placebo
(N = 4502)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or non-fatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the Cholesterol and Recurrent Events (CARE)3 study the effect of PRAVACHOL,
40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159
patients (3583 men and 576 women) who had experienced a myocardial infarction in the
preceding 3–20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo
controlled study participated for an average of 4.9 years and had a mean baseline total
cholesterol of 209 mg/dL. LDL cholesterol levels in this patient population ranged from
101 mg/dL–180 mg/dL (mean = 139 mg/dL). At baseline, 84% of patients were receiving
aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile)
percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C,
TG, and HDL were -22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1
(-2.9, 12.7), respectively. Treatment with PRAVACHOL significantly reduced the rate of
first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing
revascularization procedures (PTCA, CABG), and the risk for stroke or transient
ischemic attack (TIA) (see Table 2).
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Table 2:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N = 2081)
Placebo
(N = 2078)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality or non-fatal MI*
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
<0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
*The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I)4
study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by
coronary angiography in patients with coronary disease and moderate hyper-
cholesterolemia (baseline LDL-C range = 130-190 mg/dL). In this double-blind,
multicenter, controlled clinical trial angiograms were evaluated at baseline and at three
years in 264 patients. Although the difference between pravastatin and placebo for the
primary endpoint (per-patient change in mean coronary artery diameter) and one of two
secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical
significance, for the secondary endpoint of change in minimum lumen diameter,
statistically significant slowing of disease was seen in the pravastatin treatment group
(p=0.02).
In the Regression Growth Evaluation Statin Study (REGRESS)5, the effect of pravastatin
on coronary atherosclerosis was assessed by coronary angiography in 885 patients with
angina
pectoris,
angiographically
documented
coronary
artery
disease
and
hypercholesterolemia (baseline total cholesterol range = 160-310 mg/dL). In this double-
blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at
two years in 653 patients (323 treated with pravastatin). Progression of coronary
atherosclerosis was significantly slowed in the pravastatin group as assessed by changes
in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, the Pravastatin, Lipids and Atherosclerosis in
the Carotids Study (PLAC II)6, REGRESS, and the Kuopio Atherosclerosis Prevention
Study (KAPS)7 (combined N=1891) showed that treatment with pravastatin was
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associated with a statistically significant reduction in the composite event rate of fatal and
nonfatal myocardial infarction (46 events or 6.4% for placebo versus 21 events or 2.4%
for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of
nonfatal myocardial infarction.
Primary Hypercholesterolemia (Fredrickson Type IIa and IIb)
PRAVACHOL (pravastatin sodium) is highly effective in reducing Total-C, LDL-C and
Triglycerides (TG) in patients with heterozygous familial, presumed familial combined
and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed
dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response
usually is achieved within 4 weeks. This response is maintained during extended periods
of therapy. In addition, PRAVACHOL is effective in reducing the risk of acute coronary
events in hypercholesterolemic patients with and without previous myocardial infarction.
A single daily dose is as effective as the same total daily dose given twice a day. In
multicenter, double-blind, placebo-controlled studies of patients with primary
hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 mg to
40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C
and LDL-C/HDL-C ratios (see Table 3).
In a pooled analysis of two multicenter, double-blind, placebo-controlled studies of
patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of
80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th
percentile changes from baseline in LDL-C for pravastatin 80 mg were -43% and -30%.
The efficacy results of the individual studies were consistent with the pooled data (see
Table 3).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across
all doses produced variable increases in HDL-C (see Table 3).
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Table 3:
Primary Hypercholesterolemia Studies:
Dose Response of PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeks*
Placebo (N=36)
-3%
-4%
+1%
-4%
10 mg (N=18)
-16%
-22%
+7%
-15%
20 mg (N=19)
-24%
-32%
+2%
-11%
40 mg (N=18)
-25%
-34%
+12%
-24%
Mean Percent Changes From Baseline After 6 Weeks**
Placebo (N=162)
0%
-1%
-1%
+1%
80 mg (N=277)
-27%
-37%
+3%
-19%
* a multicenter, double-blind, placebo-controlled study
**pooled analysis of 2 multicenter, double-blind, placebo-controlled studies
In another clinical trial, patients treated with pravastatin in combination with
cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had
reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated
cholestyramine-induced increases in TG levels (which are themselves of uncertain
clinical significance).
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG
> 200 mg/dL and LDL-C < 160 mg/dL) was evaluated in a subset of 429 patients from
the Cholesterol and Recurrent Events (CARE) study. For pravastatin-treated subjects, the
median (min, max) baseline triglyceride level was 246.0 (200.5, 349.5) mg/dL. (See
Table 4.)
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Table 4:
Patients With Fredrickson Type IV Hyperlipidemia
Median (25th, 75th percentile) Percent Change From Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
Triglycerides
-21.1 (-34.8, 1.3)
-6.3 (-23.1, 18.3)
Total-C
-22.1 (-27.1, -14.8)
0.2 (-6.9, 6.8)
LDL-C
-31.7 (-39.6, -21.5)
0.7 (-9.0, 10.0)
HDL-C
7.4 (-1.2, 17.7)
2.8 (-5.7, 11.7)
Non-HDL-C
-27.2 (-34.0, -18.5)
-0.8 (-8.2, 7.0)
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with
genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 5.
Table 5:
Patients With Fredrickson Type III Dysbetalipoproteinemia
Median (min, max) Percent Change From Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
-32.7 (-58.5, 4.6)
Triglycerides
443.0 (275.0, 1299.0)
-23.7 (-68.5, 44.7)
VLDL-C*
206.5 (110.0, 379.0)
-43.8 (-73.1, -14.3)
LDL-C*
117.5 (80.0, 170.0)
-40.8 (-63.7, 4.6)
HDL-C
30.0 (18.0, 88.0)
6.4 (-45.0, 105.6)
Non-HDL-C
344.5 (215.0, 646.0)
-36.7 (-66.3, 5.8)
*N=14
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
-31.4 (-54.5, -13.0)
Triglycerides
343.2 (212.6, 845.9)
-11.9 (-56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
-35.7 (-74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
-30.3 (-52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (-17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
-35.5 (-81.0, -13.5)
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Pediatric Clinical Study
A double-blind placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8-18 years was conducted for
two (2) years. The children (aged 8-13 years) were randomized to placebo (n=63) or
20 mg of pravastatin daily (n=65) and the adolescents (aged 14-18 years) were
randomized to placebo (n=45) or 40 mg of pravastatin daily (n=41). Inclusion in the
study required an LDL-C level >95th percentile for age and sex and one parent with either
a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline
LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151-405 mg/dL)
and placebo (range: 154-375 mg/dL) groups, respectively.
Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and apolipoprotein
B in both children and adolescents (see Table 6). The effect of pravastatin treatment in
the two age groups was similar.
Table 6:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients with
Heterozygous Familial Hypercholesterolemia: Least-Squares
Mean Percent Change from Baseline at Month 24 (Last
Observation Carried Forward: Intent-to-Treat)*
Pravastatin
20-mg
(Aged 8-13
years)
N = 65
Pravastatin
40-mg
(Aged 14-18
years)
N = 41
Combined
Pravastatin
(Aged 8-18
years)
N = 106
Combined
Placebo
(Aged 8-18
years)
N = 108
95% CI of the
Difference
Between
Combined
Pravastatin and
Placebo
LDL-C
-26.04**
-21.07**
-24.07**
-1.52
(-26.74, -18.86)
TC
-20.75**
-13.08**
-17.72**
-0.65
(-20.40, -13.83)
HDL-C
1.04
13.71
5.97
3.13
(-1.71, 7.43)
TG
-9.58
-0.30
-5.88
-3.27
(-13.95, 10.01)
ApoB
(N)
-23.16**
(61)
-18.08**
(39)
-21.11**
(100)
-0.97
(106)
(-24.29, -16.18)
* The above least-squares mean values were calculated based on log-transformed lipid values.
** Significant at p≤0.0001 when compared with placebo
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin
group compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
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The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in
children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity
and mortality in adulthood has not been established.
INDICATIONS AND USAGE
Therapy with PRAVACHOL (pravastatin sodium) should be considered in those
individuals at increased risk for atherosclerosis-related clinical events as a function of
cholesterol level, the presence or absence of coronary heart disease, and other risk
factors.
Primary Prevention of Coronary Events
In hypercholesterolemic patients without clinically evident coronary heart disease,
PRAVACHOL (pravastatin sodium) is indicated to:
– Reduce the risk of myocardial infarction
– Reduce the risk of undergoing myocardial revascularization procedures
– Reduce the risk of cardiovascular mortality with no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In patients with clinically evident coronary heart disease, PRAVACHOL (pravastatin
sodium) is indicated to:
– Reduce the risk of total mortality by reducing coronary death
– Reduce the risk of myocardial infarction
– Reduce the risk of undergoing myocardial revascularization procedures
– Reduce the risk of stroke and stroke/transient ischemic attack (TIA)
– Slow the progression of coronary atherosclerosis.
Hyperlipidemia
PRAVACHOL is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C,
Apo B, and TG levels and to increase HDL-C in patients with primary hyper-
cholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb)8.
PRAVACHOL is indicated as adjunctive therapy to diet for the treatment of patients with
elevated serum triglyceride levels (Fredrickson Type IV).
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PRAVACHOL
is
indicated
for
the
treatment
of
patients
with
primary
dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
PRAVACHOL is indicated as an adjunct to diet and life-style modification for treatment
of HeFH in children and adolescent patients ages 8 years and older if after an adequate
trial of diet the following findings are present:
1. LDL-C remains ≥190 mg/dL or
2. LDL-C remains ≥160 mg/dL and:
• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the patient.
Lipid-altering agents should be used in addition to a diet restricted in saturated fat and
cholesterol when the response to diet and other nonpharmacological measures alone has
been inadequate (see NCEP Guidelines below).
Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia
(e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome,
dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be
excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients
with triglycerides (TG) <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the
following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C
concentrations should be determined by ultracentrifugation. In many hypertri-
glyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such
cases, HMG-CoA reductase inhibitors are not indicated.
Lipid determinations should be performed at intervals of no less than four weeks and
dosage adjusted according to the patient’s response to therapy.
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The National Cholesterol Education Program’s Treatment Guidelines are summarized
below:
Table 7:
NCEP Treatment Guidelines: LDL-C Goals and Cutpoints
for Therapeutic Lifestyle Changes and Drug Therapy in
Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHDa or CHD risk
equivalents
(10-year risk >20%)
<100
≥100
≥130
(100-129: drug optional)b
10-year risk 10%-20%: ≥130
2+ Risk factors
(10-year risk ≤20 %)
<130
≥130
10-year risk <10%: ≥160
0 -1 Risk factorc
<160
≥160
≥190
(160-189: LDL-lowering
drug optional)
a CHD, coronary heart disease.
b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of
<100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that
primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may
call for deferring drug therapy in this subcategory.
c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people
with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C
(Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are
set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to
initiating drug therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines,
above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels
be used to initiate and assess treatment response. Only if LDL-C levels are not available,
should the Total-C be used to monitor therapy.
As with other lipid-lowering therapy, PRAVACHOL (pravastatin sodium) is not
indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated
HDL-C).
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The NCEP classification of cholesterol levels in pediatric patients with a familial history
of hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations of serum transaminases (see
WARNINGS).
Pregnancy and Lactation. Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome of long-
term therapy of primary hypercholesterolemia. Cholesterol and other products of
cholesterol biosynthesis are essential components for fetal development (including
synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors
decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in
nursing mothers. Pravastatin should be administered to women of childbearing age
only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. If the patient becomes pregnant while taking this class of drug,
therapy should be discontinued immediately and the patient apprised of the potential
hazard to the fetus (see PRECAUTIONS: Pregnancy).
WARNINGS
Liver Enzymes
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been
associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9
years), placebo-controlled clinical trials (WOS, LIPID, CARE; see CLINICAL
PHARMACOLOGY: Clinical Studies), 19,592 subjects (19,768 randomized), were
exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT,
AST), incidences of marked abnormalities were compared between the pravastatin and
placebo treatment groups; a marked abnormality was defined as a post-treatment test
value greater than three times the upper limit of normal for subjects with pretreatment
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values less than or equal to the upper limit of normal, or four times the pretreatment value
for subjects with pretreatment values greater than the upper limit of normal but less than
1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with
similar low frequency (≤1.2%) in both treatment groups. Overall, clinical trial experience
showed that liver function test abnormalities observed during pravastatin therapy were
usually asymptomatic, not associated with cholestasis, and did not appear to be related to
treatment duration.
It is recommended that liver function tests be performed prior to the initiation of
therapy, prior to the elevation of the dose, and when otherwise clinically indicated.
Active
liver
disease
or
unexplained
persistent
transaminase
elevations
are
contraindications to the use of pravastatin (see CONTRAINDICATIONS). Caution
should be exercised when pravastatin is administered to patients who have a recent
history of liver disease, have signs that may suggest liver disease (e.g., unexplained
aminotransferase elevations, jaundice), or are heavy users of alcohol (see CLINICAL
PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely
monitored, started at the lower end of the recommended dosing range, and titrated to the
desired therapeutic effect.
Patients who develop increased transaminase levels or signs and symptoms of liver
disease should be monitored with a second liver function evaluation to confirm the
finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) return to normal. Should an increase in AST or ALT of three times the
upper limit of normal or greater persist, withdrawal of pravastatin therapy is
recommended.
Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria
have been reported with pravastatin and other drugs in this class. Uncomplicated
myalgia has also been reported in pravastatin-treated patients (see ADVERSE
REACTIONS). Myopathy, defined as muscle aching or muscle weakness in conjunction
with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper
limit of normal, was rare (<0.1%) in pravastatin clinical trials. Myopathy should be
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or
marked elevation of CPK. Patients should be advised to report promptly unexplained
muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
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Pravastatin therapy should be discontinued if markedly elevated CPK levels occur
or myopathy is diagnosed or suspected. Pravastatin therapy should also be
temporarily withheld in any patient experiencing an acute or serious condition
predisposing to the development of renal failure secondary to rhabdomyolysis, e.g.,
sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or
electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is
increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or
fibrates. However, neither myopathy nor significant increases in CPK levels have been
observed in three reports involving a total of 100 post-transplant patients (24 renal and 76
cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and
cyclosporine. Some of these patients also received other concomitant immunosuppressive
therapies. Further, in clinical trials involving small numbers of patients who were treated
concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and
gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked
CPK elevations versus one of 73 patients receiving placebo. There was a trend toward
more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms
in the group receiving combined treatment as compared with the groups receiving
placebo, gemfibrozil, or pravastatin monotherapy (see PRECAUTIONS: Drug
Interactions). The use of fibrates alone may occasionally be associated with
myopathy. The combined use of pravastatin and fibrates should be avoided unless
the benefit of further alterations in lipid levels is likely to outweigh the increased
risk of this drug combination.
PRECAUTIONS
General
PRAVACHOL (pravastatin sodium) may elevate creatine phosphokinase and
transaminase levels (see ADVERSE REACTIONS). This should be considered in the
differential diagnosis of chest pain in a patient on therapy with pravastatin.
Homozygous Familial Hypercholesterolemia. Pravastatin has not been evaluated in
patients with rare homozygous familial hypercholesterolemia. In this group of patients, it
has been reported that HMG-CoA reductase inhibitors are less effective because the
patients lack functional LDL receptors.
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Renal Insufficiency. A single 20 mg oral dose of pravastatin was administered to 24
patients with varying degrees of renal impairment (as determined by creatinine
clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-
hydroxy isomeric metabolite (SQ 31,906). A small increase was seen in mean AUC
values and half-life (t½) for the inactive enzymatic ring hydroxylation metabolite
(SQ 31,945). Given this small sample size, the dosage administered, and the degree of
individual variability, patients with renal impairment who are receiving pravastatin
should be closely monitored.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever (see WARNINGS: Skeletal
Muscle).
Drug Interactions
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See
WARNINGS: Skeletal Muscle.
Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is
not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been
shown in studies with known cytochrome P450 3A4 inhibitors (see diltiazem and
itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include
ketoconazole, mibefradil, and erythromycin.
Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had
no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of
another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome
P450 3A4 increased by factors of 3.6 and 4.3, respectively.
Itraconazole: The mean AUC and Cmax for pravastatin were increased by factors of 1.7
and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which
also inhibits p-glycoprotein transport) as compared to placebo. The mean t½ was not
affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC
were due solely to increased bioavailability rather than a decrease in clearance, consistent
with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is
thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors,
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including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19
and 17, respectively, when given with itraconazole.
Antipyrine: Since concomitant administration of pravastatin had no effect on the
clearance of antipyrine, interactions with other drugs metabolized via the same hepatic
cytochrome isozymes are not expected.
Cholestyramine/Colestipol: Concomitant administration resulted in an approximately
40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was
administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol
and a standard meal, there was no clinically significant decrease in bioavailability or
therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant
Therapy.)
Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant
effect on prothrombin time when administered in a study to normal elderly subjects who
were stabilized on warfarin.
Cimetidine: The AUC0-12hr for pravastatin when given with cimetidine was not
significantly different from the AUC for pravastatin when given alone. A significant
difference was observed between the AUC’s for pravastatin when given with cimetidine
compared to when administered with antacid.
Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin
and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin
were not affected. The AUC of pravastatin tended to increase, but the overall
bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not
altered.
Cyclosporine: Some investigators have measured cyclosporine levels in patients on
pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful
elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found
to be increased in cardiac transplant patients receiving cyclosporine.
Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant
single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary
excretion and protein binding of pravastatin. In addition, there was a significant increase
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in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906. Combination therapy
with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS:
Skeletal Muscle.)
In interaction studies with aspirin, antacids (1 hour prior to PRAVACHOL), cimetidine,
nicotinic acid, or probucol, no statistically significant differences in bioavailability were
seen when PRAVACHOL (pravastatin sodium) was administered.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating
cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid
hormone production. Results of clinical trials with pravastatin in males and post-
menopausal females were inconsistent with regard to possible effects of the drug on basal
steroid hormone levels. In a study of 21 males, the mean testosterone response to human
chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment
with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change
significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors
on spermatogenesis and fertility have not been studied in adequate numbers of patients.
The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females
are unknown. Patients treated with pravastatin who display clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may diminish the levels or activity of steroid hormones.
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were
treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the
adolescents aged 14-18 years) for two years, there were no detectable differences seen in
any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol
(girls) or testosterone (boys)] relative to placebo. There were no detectable differences
seen in height and weight changes, testicular volume changes, or Tanner score relative to
placebo.
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CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and
mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with
pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at
approximately 59 times the human dose of 80 mg/day, based on AUC. Similar CNS
vascular lesions have been observed with several other drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30
times higher than the mean drug level in humans taking the highest recommended dose
(as measured by total enzyme inhibitory activity). This same drug also produced
vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in
dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug
level similar to that seen with the 60 mg/kg/day dose.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight,
there was an increased incidence of hepatocellular carcinomas in males at the highest
dose (p <0.01). These effects in rats were observed at approximately 12 times the human
dose (HD) of 80 mg based on body surface area mg/m2 and at approximately 4 times the
human dose, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased
(p=0.013). These effects in mice were observed at approximately 15 times
(250 mg/kg/day) and 23 times (500 mg/kg/day) the human dose of 80 mg, based on
AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug
exposures approximately 2 times the human dose of 80 mg, based on AUC), there were
no drug-induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of
Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/-
mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene
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conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of
mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.
In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance. However, in a study with
another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated
for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a
subsequent fertility study when this same dose was administered for 11 weeks (the entire
cycle of spermatogenesis, including epididymal maturation). In rats treated with this
same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis
and loss of spermatogenic epithelium) was observed. Although not seen with pravastatin,
two similar drugs in this class caused drug-related testicular atrophy, decreased
spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The
clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X.
See CONTRAINDICATIONS.
Safety in pregnant women has not been established. Pravastatin was not teratogenic in
rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These
doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area
(mg/meter2). Rare reports of congenital anomalies have been received following
intrauterine exposure to other HMG-CoA reductase inhibitors. In a review9 of
approximately 100 prospectively followed pregnancies in women exposed to simvastatin
or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal
deaths/stillbirths did not exceed what would be expected in the general population. The
number of cases is adequate only to exclude a three-to-four-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at
some point in the first trimester when pregnancy was identified. As safety in pregnant
women has not been established and there is no apparent benefit to therapy with
PRAVACHOL during pregnancy (see CONTRAINDICATIONS), treatment should be
immediately discontinued as soon as pregnancy is recognized. PRAVACHOL
(pravastatin sodium) should be administered to women of child-bearing potential only
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when such patients are highly unlikely to conceive and have been informed of the
potential hazards.
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential
for serious adverse reactions in nursing infants, women taking PRAVACHOL should not
nurse (see CONTRAINDICATIONS).
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8-18
years of age have been evaluated in a placebo-controlled study of 2 years duration.
Patients treated with pravastatin had an adverse experience profile generally similar to
that of patients treated with placebo with influenza and headache commonly reported in
both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses
greater than 40 mg have not been studied in this population. Children and adolescent
females of childbearing potential should be counseled on appropriate contraceptive
methods
while
on
pravastatin
therapy
(see
CONTRAINDICATIONS
and
PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND
ADMINISTRATION: Adult Patients and Pediatric Patients.
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age
have not been conducted.
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of
6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across
these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were
aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing
cardiovascular events and in modifying lipid profiles was similar to that seen in younger
subjects. The adverse event profile in the elderly was similar to that in the overall
population. Other reported clinical experience has not identified differences in responses
to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy
young subjects, but mean Cmax, Tmax and t½ values are similar in both age groups and
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substantial accumulation of pravastatin would not be expected in the elderly (see
CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism).
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and
transient. In 4-month long placebo-controlled trials, 1.7% of pravastatin-treated patients
and 1.2% of placebo-treated patients were discontinued from treatment because of
adverse experiences attributed to study drug therapy; this difference was not statistically
significant. (See also PRECAUTIONS: Geriatric Use section.)
Adverse Clinical Events
Short-Term Controlled Trials
All adverse clinical events (regardless of attribution) reported in more than 2% of
pravastatin-treated patients in placebo-controlled trials of up to four months duration are
identified in Table 8; also shown are the percentages of patients in whom these medical
events were believed to be related or possibly related to the drug:
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Table 8:
Adverse Events in >2 Percent of Patients Treated with
Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials
All Events
Events Attributed
to Study Drug
Body System/Event
Pravastatin
(N = 900)
% of patients
Placebo
(N = 411)
% of patients
Pravastatin
(N = 900)
% of patients
Placebo
(N = 411)
% of patients
Cardiovascular
Cardiac Chest Pain
4.0
3.4
0.1
0.0
Dermatologic
Rash
4.0*
1.1
1.3
0.9
Gastrointestinal
Nausea/Vomiting
Diarrhea
Abdominal Pain
Constipation
Flatulence
Heartburn
7.3
6.2
5.4
4.0
3.3
2.9
7.1
5.6
6.9
7.1
3.6
1.9
2.9
2.0
2.0
2.4
2.7
2.0
3.4
1.9
3.9
5.1
3.4
0.7
General
Fatigue
Chest Pain
Influenza
3.8
3.7
2.4*
3.4
1.9
0.7
1.9
0.3
0.0
1.0
0.2
0.0
Musculoskeletal
Localized Pain
Myalgia
10.0
2.7
9.0
1.0
1.4
0.6
1.5
0.0
Nervous System
Headache
Dizziness
6.2
3.3
3.9
3.2
1.7*
1.0
0.2
0.5
Renal/Genitourinary
Urinary Abnormality
2.4
2.9
0.7
1.2
Respiratory
Common Cold
Rhinitis
Cough
7.0
4.0
2.6
6.3
4.1
1.7
0.0
0.1
0.1
0.0
0.0
0.0
*Statistically significantly different from placebo.
The safety and tolerability of PRAVACHOL at a dose of 80 mg in two controlled trials
with a mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses
except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of
CK >10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.
Long-Term Controlled Morbidity and Mortality Trials
Adverse event data were pooled from seven double-blind, placebo-controlled trials (West
of Scotland Coronary Prevention study [WOS]; Cholesterol and Recurrent Events study
[CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID];
Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I];
Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression
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Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention
Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and
10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin
group was comparable to that of the placebo group. Patients were exposed to pravastatin
for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I,
PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for
discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these
seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to
be of probable, possible, or uncertain relationship to study drug, occurring in at least 1%
of patients treated with pravastatin in these studies are identified in Table 9.
Table 9:
Adverse Events in ≥1 Percent of Patients Treated with Pravastatin
40 mg in Long-Term Placebo-Controlled Trials
Body System/Event
Pravastatin
(N = 10,764)
% of patients
Placebo
(N = 10,719)
% of patients
Cardiovascular
Angina Pectoris
3.1
3.4
Dermatologic
Rash
2.1
2.2
Gastrointestinal
Dyspepsia/Heartburn
Abdominal Pain
Nausea/Vomiting
Flatulence
Constipation
3.5
2.4
1.6
1.2
1.2
3.7
2.5
1.6
1.1
1.3
General
Fatigue
Chest Pain
3.4
2.6
3.3
2.6
Musculoskeletal
Musculoskeletal Pain (includes arthralgia)
Muscle Cramp
Myalgia
6.0
2.0
1.4
5.8
1.8
1.4
Nervous System
Dizziness
Headache
Sleep Disturbance
Depression
Anxiety/Nervousness
2.2
1.9
1.0
1.0
1.0
2.1
1.8
0.9
1.0
1.2
Renal/Genitourinary
Urinary Abnormality (includes dysuria, frequency, nocturia)
1.0
0.8
Respiratory
Dyspnea
Upper Respiratory Infection
Cough
1.6
1.3
1.0
1.6
1.3
1.0
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
1.6
1.3
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Events of probable, possible, or uncertain relationship to study drug that occurred in
<1.0% of pravastatin-treated patients in the long-term trials included the following;
frequencies were similar in placebo-treated patients:
Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including
alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
Gastrointestinal: decreased appetite.
General: fever, flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy
(including peripheral neuropathy).
Special Senses: lens opacity, taste disturbance.
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following
events have been reported rarely during postmarketing experience with PRAVACHOL,
regardless of causality assessment:
Musculoskeletal: myopathy, rhabdomyolysis.
Nervous System: dysfunction of certain cranial nerves (including alteration of taste,
impairment of extra-ocular movement, facial paresis), peripheral nerve palsy.
Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome,
polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia,
positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills,
malaise, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson
syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic
jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma.
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Dermatologic: A variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Reproductive: gynecomastia.
Laboratory Abnormalities: LFT abnormalities, thyroid function abnormalities.
Laboratory Test Abnormalities
Increases in serum transaminase (ALT, AST) values and CPK have been observed (see
WARNINGS).
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually
returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia
have been reported with HMG-CoA reductase inhibitors.
Concomitant Therapy
Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic
acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either
probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with
greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin
alone. No adverse reactions unique to the combination or in addition to those previously
reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or
without acute renal failure) have been reported when another HMG-CoA reductase
inhibitor was used in combination with immunosuppressive drugs, gemfibrozil,
erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-
CoA reductase inhibitors and these agents is generally not recommended. (See
WARNINGS: Skeletal Muscle and PRECAUTIONS: Drug Interactions.)
Pediatric Patients
In a two year double-blind placebo-controlled study involving 100 boys and 114 girls
with HeFH, the safety and tolerability profile of pravastatin was generally similar to that
of placebo. (See CLINICAL PHARMACOLOGY, Pediatric Clinical Study and
PRECAUTIONS, Pediatric Use.)
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OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose
occurs, it should be treated symptomatically with laboratory monitoring and supportive
measures should be instituted as required. (See WARNINGS.)
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL (pravastatin sodium) and should continue on this diet during treatment
with PRAVACHOL (see NCEP Treatment Guidelines for details on dietary therapy).
PRAVACHOL can be administered orally as a single dose at any time of the day, with or
without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic
lipid determinations should be performed at this time and dosage adjusted according to
the patient’s response to therapy and established treatment guidelines.
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not
achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a
history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is
recommended.
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses
greater than 20 mg have not been studied in this patient population.
Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age.
Doses greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be reevaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C (see INDICATIONS AND USAGE, Hyperlipidemia, NCEP Treatment
Guidelines).
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In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS:
Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of
pravastatin once-a-day at bedtime and titration to higher doses should be done with
caution. Most patients treated with this combination received a maximum pravastatin
dose of 20 mg/day.
Concomitant Therapy
The lipid-lowering effects of PRAVACHOL on total and LDL cholesterol are enhanced
when combined with a bile-acid-binding resin. When administering a bile-acid-binding
resin (e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given
either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE
REACTIONS: Concomitant Therapy.)
HOW SUPPLIED
PRAVACHOL® (pravastatin sodium) Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P”
embossed on one side and “PRAVACHOL 10” engraved on the opposite side. They are
supplied in bottles of 90 (NDC 0003-5154-05). Bottles contain a desiccant canister.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 20” engraved on the opposite side. They are supplied in
bottles of 90 (NDC 0003-5178-05), bottles of 1000 (NDC 0003-5178-75), and hospital
unit-dose packages of 100 tablets (NDC 0003-5178-06). Bottles contain a desiccant
canister.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 40” engraved on the opposite side. They are supplied in
bottles of 90 (NDC 0003-5194-10) and hospital unit-dose packages of 100 tablets (NDC
0003-5194-33). Bottles contain a desiccant canister.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other
side. They are supplied in bottles of 90 (NDC 0003-5195-10), bottles of 500 (NDC
0003-5195-12), and hospital unit-dose packages of 100 tablets (NDC 0003-5195-33).
Bottles contain a desiccant canister.
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STORAGE
Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F) [see USP
Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect
from light.
REFERENCES
1 Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in Men with
Hypercholesterolemia (WOS). N Engl J Med 1995;333:1301–7.
2 The Long-term Intervention with Pravastatin in Ischemic Disease Group. Prevention
of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart
Disease and a Broad Range of Initial Cholesterol Levels (LIPID). N Engl J Med
1998;339:1349–1357.
3 Sacks FM, et al. The Effect of Pravastatin on Coronary Events After Myocardial
Infarction in Patients with Average Cholesterol Levels (CARE). N Engl J Med
1996;335:1001-9.
4 Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries
(PLAC I): Reduction in Atherosclerosis Progression and Clinical Events. J Am Coll
Cardiol 1995;26:1133-9.
5 Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression and
Regression of Coronary Artery Disease in Symptomatic Man With Normal to
Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation
Statin Study (REGRESS). Circulation 1995;91:2528–2540.
6 Crouse JR, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries:
Design Features of a Clinical Trial with Carotid Atherosclerosis Outcome (PLAC II).
Controlled Clinical Trials 1992;13:495.
7 Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A Population-
based Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic
Progression in Carotid and Femoral Arteries. Research Institute of Public Health,
University of Kuopio, Finland. Circulation 1995;92:1758.
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8 Fredrickson DS, et al. Fat Transport in Lipoproteins-An Integrated Approach to
Mechanisms and Disorders. N Engl J Med 1967;276:34-42, 94-102, 148-156, 215-
224, 273-281.
9 Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing
Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive
Toxicology 1996;10(6):439-446.
US Patent Nos.: 4,346,227; 5,030,447; 5,180,589; 5,622,985
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
5154DIM-25
1187948
J4-538Y
519590DIM-03
1186935
J4-701B
Revised December 2004
1187947
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2025-02-12T13:46:15.295783
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019898s058lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 58}
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11,826
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Rx only
PRAVACHOL®
(pravastatin sodium) Tablets
DESCRIPTION
PRAVACHOL® (pravastatin sodium) is one of a class of lipid-lowering compounds, the
HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis. These agents are
competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid,
1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula:
C23H35NaO7 MW 446.52
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a
relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59
at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in
isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg
tablets. Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide,
magnesium stearate, microcrystalline cellulose, and povidone. The 10 mg tablet also
contains Red Ferric Oxide, the 20 mg and 80 mg tablets also contain Yellow Ferric
Oxide, and the 40 mg tablet also contains Green Lake Blend (mixture of D&C Yellow
No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).
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CLINICAL PHARMACOLOGY
Cholesterol and triglycerides in the bloodstream circulate as part of lipoprotein
complexes. These complexes can be separated by density ultracentrifugation into high
(HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein
fractions. Triglycerides (TG) and cholesterol synthesized in the liver are incorporated into
very low density lipoproteins (VLDLs) and released into the plasma for delivery to
peripheral tissues. In a series of subsequent steps, VLDLs are transformed into
intermediate density lipoproteins (IDLs), and cholesterol-rich low density lipoproteins
(LDLs). High density lipoproteins (HDLs), containing apolipoprotein A, are
hypothesized to participate in the reverse transport of cholesterol from tissues back to the
liver.
PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of
its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in
intracellular pools of cholesterol. This results in an increase in the number of LDL-
receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of
circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic
synthesis of VLDL, the LDL precursor.
Clinical and pathologic studies have shown that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB − a
membrane transport complex for LDL) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein
A, are associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with the level
of Total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-
enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also
promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low
HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic
risk factors for coronary heart disease. As such, total plasma TG has not consistently been
shown to be an independent risk factor for CHD. Furthermore, the independent effect of
raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and
mortality has not been determined. In both normal volunteers and patients with
hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and
apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases
in HDL-C and apolipoprotein A. The effects of pravastatin on Lp (a), fibrinogen, and
certain other independent biochemical risk markers for coronary heart disease are
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unknown. Although pravastatin is relatively more hydrophilic than other HMG-CoA
reductase inhibitors, the effect of relative hydrophilicity, if any, on either efficacy or
safety has not been established.
In one primary (West of Scotland Coronary Prevention Study - WOS)1 and two
secondary (Long-term Intervention with Pravastatin in Ischemic Disease - LIPID2 and the
Cholesterol and Recurrent Events - CARE3) prevention studies, PRAVACHOL has been
shown to reduce cardiovascular morbidity and mortality across a wide range of
cholesterol levels (see Clinical Studies).
Pharmacokinetics/Metabolism
PRAVACHOL (pravastatin sodium) is administered orally in the active form. In clinical
pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of
parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery
of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute
bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken
with, or 1 hour prior to, meals.
Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66),
which is its primary site of action, and the primary site of cholesterol synthesis and of
LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into
hepatocytes with substantially less uptake into other cells. In view of pravastatin’s
apparently extensive first-pass hepatic metabolism, plasma levels may not necessarily
correlate perfectly with lipid-lowering efficacy. Pravastatin plasma concentrations
[including: area under the concentration-time curve (AUC), peak (Cmax), and steady-state
minimum (Cmin)] are directly proportional to administered dose. Systemic bioavailability
of pravastatin administered following a bedtime dose was decreased 60% compared to
that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy
of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose. This finding of
lower systemic bioavailability suggests greater hepatic extraction of the drug following
the evening dose. Steady-state AUCs, Cmax and Cmin plasma concentrations showed no
evidence of pravastatin accumulation following once or twice daily administration of
PRAVACHOL tablets. Approximately 50% of the circulating drug is bound to plasma
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proteins. Following single dose administration of 14C-pravastatin, the elimination half-
life (t½) for total radioactivity (pravastatin plus metabolites) in humans is 77 hours.
Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The
coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. Pravastatin 20 mg was administered under fasting conditions in adults. The
geometric means of Cmax and AUC ranged from 23.3 to 26.3 ng/mL and from 54.7 to
62.2 ng*hr/mL, respectively.
Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.
After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal
routes (i.e., biliary excretion and biotransformation). Since there are dual routes of
elimination, the potential exists both for compensatory excretion by the alternate route as
well as for accumulation of drug and/or metabolites in patients with renal or hepatic
insufficiency.
In a study comparing the kinetics of pravastatin in patients with biopsy confirmed
cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied
47-fold for cirrhotic patients compared to 6-fold for healthy subjects.
Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi
pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring
hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of
the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a
hydroxyl group to a keto group, and (g) conjugation. The major degradation product is
the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA
reductase inhibitory activity of the parent compound.
In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was
approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65 to 75 years old) compared with younger
men (19 to 31 years old). In a similar study conducted in women, the mean AUC for
pravastatin was approximately 46% higher and the mean CUE approximately 18% lower
in elderly women (65 to 78 years old) compared with younger women (18 to 38 years
old). In both studies, Cmax, Tmax and t½ values were similar in older and younger subjects.
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After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means
of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for
Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents,
respectively. No conclusion can be made based on these findings due to the small number
of samples and large variability.
Clinical Studies
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (West of Scotland Coronary Prevention
Study – WOS)1, the effect of PRAVACHOL on fatal and nonfatal coronary heart disease
(CHD) was assessed in 6595 men 45–64 years of age, without a previous myocardial
infarction (MI), and with LDL-C levels between 156–254 mg/dL (4–6.7 mmol/L). In this
randomized, double-blind, placebo-controlled study, patients were treated with standard
care, including dietary advice, and either PRAVACHOL 40 mg daily (N=3302) or
placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th
percentile) percent changes from baseline after 6 months of pravastatin treatment in
Total-C, LDL-C, TG, and HDL-C were -20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1
(-27.6, 12.5), and 6.7 (-2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either coronary
heart disease [CHD] death or nonfatal MI) by 31% [248 events in the placebo group
(CHD death=44, nonfatal MI=204) vs 174 events in the PRAVACHOL group (CHD
death=31, nonfatal MI=143), p=0.0001 (see figure below)]. The risk reduction with
PRAVACHOL was similar and significant throughout the entire range of baseline LDL
cholesterol levels. This reduction was also similar and significant across the age range
studied with a 40% risk reduction for patients younger than 55 years and a 27% risk
reduction for patients 55 years and older. The Pravastatin Primary Prevention Study
included only men, and therefore it is not clear to what extent these data can be
extrapolated to a similar population of female patients.
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PRAVACHOL also significantly decreased the risk for undergoing myocardial
revascularization procedures (coronary artery bypass graft [CABG] surgery or
percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients,
p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths
were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)2 study, the
effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients (7498 men; 1516
women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina
pectoris (3260 patients) in the preceding 3-36 months. Patients in this multicenter,
double-blind, placebo-controlled study participated for an average of 5.6 years (median
of 5.9 years) and at randomization had total cholesterol between 114 and 563 mg/dL
(mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), triglycerides
between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL
(mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were
receiving antihypertensive medication. Treatment with PRAVACHOL significantly
reduced the risk for total mortality by reducing coronary death (see Table 1). The risk
reduction due to treatment with PRAVACHOL on CHD mortality was consistent
regardless of age. PRAVACHOL significantly reduced the risk for total mortality (by
reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who
qualified with a history of either MI or hospitalization for unstable angina pectoris.
6
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Table 1:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N=4512)
Placebo
(N=4502)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or nonfatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the Cholesterol and Recurrent Events (CARE)3 study the effect of PRAVACHOL,
40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159
patients (3583 men and 576 women) who had experienced a myocardial infarction in the
preceding 3-20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo-
controlled study participated for an average of 4.9 years and had a mean baseline total
cholesterol of 209 mg/dL. LDL-cholesterol levels in this patient population ranged from
101 mg/dL–180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving
aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile)
percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C,
TG, and HDL-C were -22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1
(-2.9, 12.7), respectively. Treatment with PRAVACHOL significantly reduced the rate of
first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing
revascularization procedures (PTCA, CABG), and the risk for stroke or transient
ischemic attack (TIA) (see Table 2).
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Table 2:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin
40 mg
(N=2081)
Placebo
(N=2078)
Risk
Reduction
P-value
Primary Endpoint
CHD mortality or nonfatal MI*
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
<0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
*The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I)4
study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by
coronary angiography in patients with coronary disease and moderate hyper-
cholesterolemia (baseline LDL-C range: 130-190 mg/dL). In this double-blind,
multicenter, controlled clinical trial, angiograms were evaluated at baseline and at three
years in 264 patients. Although the difference between pravastatin and placebo for the
primary endpoint (per-patient change in mean coronary artery diameter) and one of two
secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical
significance, for the secondary endpoint of change in minimum lumen diameter,
statistically significant slowing of disease was seen in the pravastatin treatment group
(p=0.02).
In the Regression Growth Evaluation Statin Study (REGRESS)5, the effect of pravastatin
on coronary atherosclerosis was assessed by coronary angiography in 885 patients with
angina
pectoris,
angiographically
documented
coronary
artery
disease
and
hypercholesterolemia (baseline total cholesterol range: 160-310 mg/dL). In this double-
blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at
two years in 653 patients (323 treated with pravastatin). Progression of coronary
atherosclerosis was significantly slowed in the pravastatin group as assessed by changes
in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, the Pravastatin, Lipids and Atherosclerosis in
the Carotids Study (PLAC II)6, REGRESS, and the Kuopio Atherosclerosis Prevention
Study (KAPS)7 (combined N=1891) showed that treatment with pravastatin was
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9
associated with a statistically significant reduction in the composite event rate of fatal and
nonfatal myocardial infarction (46 events or 6.4% for placebo versus 21 events or 2.4%
for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of
nonfatal myocardial infarction.
Primary Hypercholesterolemia (Fredrickson Type IIa and IIb)
PRAVACHOL (pravastatin sodium) is highly effective in reducing Total-C, LDL-C and
triglycerides (TG) in patients with heterozygous familial, presumed familial combined
and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed
dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response
usually is achieved within 4 weeks. This response is maintained during extended periods
of therapy. In addition, PRAVACHOL is effective in reducing the risk of acute coronary
events in hypercholesterolemic patients with and without previous myocardial infarction.
A single daily dose is as effective as the same total daily dose given twice a day. In
multicenter, double-blind, placebo-controlled studies of patients with primary
hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 mg to
40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C
and LDL-C/HDL-C ratios (see Table 3).
In a pooled analysis of two multicenter, double-blind, placebo-controlled studies of
patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of
80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th
percentile changes from baseline in LDL-C for pravastatin 80 mg were -43% and -30%.
The efficacy results of the individual studies were consistent with the pooled data (see
Table 3).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across
all doses produced variable increases in HDL-C (see Table 3).
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Table 3:
Primary Hypercholesterolemia Studies:
Dose Response of PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeks*
Placebo (N=36)
-3%
-4%
+1%
-4%
10 mg (N=18)
-16%
-22%
+7%
-15%
20 mg (N=19)
-24%
-32%
+2%
-11%
40 mg (N=18)
-25%
-34%
+12%
-24%
Mean Percent Changes From Baseline After 6 Weeks**
Placebo (N=162)
0%
-1%
-1%
+1%
80 mg (N=277)
-27%
-37%
+3%
-19%
* a multicenter, double-blind, placebo-controlled study
**pooled analysis of 2 multicenter, double-blind, placebo-controlled studies
In another clinical trial, patients treated with pravastatin in combination with
cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had
reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated
cholestyramine-induced increases in TG levels (which are themselves of uncertain
clinical significance).
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG
>200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the
Cholesterol and Recurrent Events (CARE) study. For pravastatin-treated subjects, the
median (min, max) baseline triglyceride level was 246.0 (200.5, 349.5) mg/dL. (See
Table 4.)
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Table 4:
Patients with Fredrickson Type IV Hyperlipidemia
Median (25th, 75th percentile) Percent Change from Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
Triglycerides
-21.1 (-34.8, 1.3)
-6.3 (-23.1, 18.3)
Total-C
-22.1 (-27.1, -14.8)
0.2 (-6.9, 6.8)
LDL-C
-31.7 (-39.6, -21.5)
0.7 (-9.0, 10.0)
HDL-C
7.4 (-1.2, 17.7)
2.8 (-5.7, 11.7)
Non-HDL-C
-27.2 (-34.0, -18.5)
-0.8 (-8.2, 7.0)
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with
genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 5.
Table 5:
Patients with Fredrickson Type III Dysbetalipoproteinemia
Median (min, max) Percent Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
-32.7 (-58.5, 4.6)
Triglycerides
443.0 (275.0, 1299.0)
-23.7 (-68.5, 44.7)
VLDL-C*
206.5 (110.0, 379.0)
-43.8 (-73.1, -14.3)
LDL-C*
117.5 (80.0, 170.0)
-40.8 (-63.7, 4.6)
HDL-C
30.0 (18.0, 88.0)
6.4 (-45.0, 105.6)
Non-HDL-C
344.5 (215.0, 646.0)
-36.7 (-66.3, 5.8)
*N=14
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
-31.4 (-54.5, -13.0)
Triglycerides
343.2 (212.6, 845.9)
-11.9 (-56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
-35.7 (-74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
-30.3 (-52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (-17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
-35.5 (-81.0, -13.5)
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Pediatric Clinical Study
A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8-18 years was conducted for
two (2) years. The children (aged 8-13 years) were randomized to placebo (N=63) or
20 mg of pravastatin daily (N=65) and the adolescents (aged 14-18 years) were
randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the
study required an LDL-C level >95th percentile for age and sex and one parent with either
a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline
LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151-405 mg/dL)
and placebo (range: 154-375 mg/dL) groups, respectively.
Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and apolipoprotein
B in both children and adolescents (see Table 6). The effect of pravastatin treatment in
the two age groups was similar.
Table 6:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients
with Heterozygous Familial Hypercholesterolemia: Least-
Squares Mean Percent Change from Baseline at Month 24
(Last Observation Carried Forward: Intent-to-Treat)*
Pravastatin
20 mg
(Aged 8-13
years)
N=65
Pravastatin
40 mg
(Aged 14-18
years)
N=41
Combined
Pravastatin
(Aged 8-18
years)
N=106
Combined
Placebo
(Aged 8-18
years)
N=108
95% CI of the
Difference
Between
Combined
Pravastatin and
Placebo
LDL-C
-26.04**
-21.07**
-24.07**
-1.52
(-26.74, -18.86)
TC
-20.75**
-13.08**
-17.72**
-0.65
(-20.40, -13.83)
HDL-C
1.04
13.71
5.97
3.13
(-1.71, 7.43)
TG
-9.58
-0.30
-5.88
-3.27
(-13.95, 10.01)
ApoB
(N)
-23.16**
(61)
-18.08**
(39)
-21.11**
(100)
-0.97
(106)
(-24.29, -16.18)
* The above least-squares mean values were calculated based on log-transformed lipid values.
** Significant at p≤0.0001 when compared with placebo
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin
group compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
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The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in
children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity
and mortality in adulthood has not been established.
INDICATIONS AND USAGE
Therapy with PRAVACHOL (pravastatin sodium) should be considered in those
individuals at increased risk for atherosclerosis-related clinical events as a function of
cholesterol level, the presence or absence of coronary heart disease, and other risk
factors.
Primary Prevention of Coronary Events
In hypercholesterolemic patients without clinically evident coronary heart disease,
PRAVACHOL is indicated to:
– Reduce the risk of myocardial infarction
– Reduce the risk of undergoing myocardial revascularization procedures
– Reduce the risk of cardiovascular mortality with no increase in death from non-
cardiovascular causes.
Secondary Prevention of Cardiovascular Events
In patients with clinically evident coronary heart disease, PRAVACHOL is indicated to:
– Reduce the risk of total mortality by reducing coronary death
– Reduce the risk of myocardial infarction
– Reduce the risk of undergoing myocardial revascularization procedures
– Reduce the risk of stroke and stroke/transient ischemic attack (TIA)
– Slow the progression of coronary atherosclerosis.
Hyperlipidemia
PRAVACHOL is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C,
ApoB, and TG levels and to increase HDL-C in patients with primary hyper-
cholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb).8
PRAVACHOL is indicated as adjunctive therapy to diet for the treatment of patients with
elevated serum triglyceride levels (Fredrickson Type IV).
PRAVACHOL
is
indicated
for
the
treatment
of
patients
with
primary
dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
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PRAVACHOL is indicated as an adjunct to diet and lifestyle modification for treatment
of HeFH in children and adolescent patients ages 8 years and older if after an adequate
trial of diet the following findings are present:
1. LDL-C remains ≥190 mg/dL or
2. LDL-C remains ≥160 mg/dL and:
• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the patient.
Lipid-altering agents should be used in addition to a diet restricted in saturated fat and
cholesterol when the response to diet and other nonpharmacological measures alone has
been inadequate (see NCEP Guidelines below).
Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia
(e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome,
dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be
excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients
with triglycerides (TG) <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the
following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C
concentrations should be determined by ultracentrifugation. In many hypertri-
glyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such
cases, HMG-CoA reductase inhibitors are not indicated.
Lipid determinations should be performed at intervals of no less than four weeks and
dosage adjusted according to the patient’s response to therapy.
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The National Cholesterol Education Program’s Treatment Guidelines are summarized
below:
Table 7:
NCEP Treatment Guidelines: LDL-C Goals and Cutpoints
for Therapeutic Lifestyle Changes and Drug Therapy in
Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHDa or CHD risk
equivalents
(10-year risk >20%)
<100
≥100
≥130
(100-129: drug optional)b
10-year risk 10%-20%: ≥130
2+ Risk factors
(10-year risk ≤20 %)
<130
≥130
10-year risk <10%: ≥160
0-1 Risk factorc
<160
≥160
≥190
(160-189: LDL-lowering
drug optional)
a CHD, coronary heart disease.
b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of
<100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that
primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may
call for deferring drug therapy in this subcategory.
c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people
with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C
(Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are
set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to
initiating drug therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines,
above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels
be used to initiate and assess treatment response. Only if LDL-C levels are not available,
should the Total-C be used to monitor therapy.
As with other lipid-lowering therapy, PRAVACHOL (pravastatin sodium) is not
indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated
HDL-C).
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The NCEP classification of cholesterol levels in pediatric patients with a familial history
of hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations of serum transaminases (see
WARNINGS).
Pregnancy and Lactation. Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome of long-
term therapy of primary hypercholesterolemia. Cholesterol and other products of
cholesterol biosynthesis are essential components for fetal development (including
synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors
decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in
nursing mothers. Pravastatin should be administered to women of childbearing age
only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. If the patient becomes pregnant while taking this class of drug,
therapy should be discontinued immediately and the patient apprised of the potential
hazard to the fetus (see PRECAUTIONS: Pregnancy).
WARNINGS
Liver Enzymes
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been
associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9
years), placebo-controlled clinical trials (WOS, LIPID, CARE; see CLINICAL
PHARMACOLOGY: Clinical Studies), 19,592 subjects (19,768 randomized), were
exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT,
AST), incidences of marked abnormalities were compared between the pravastatin and
placebo treatment groups; a marked abnormality was defined as a post-treatment test
value greater than three times the upper limit of normal for subjects with pretreatment
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values less than or equal to the upper limit of normal, or four times the pretreatment value
for subjects with pretreatment values greater than the upper limit of normal but less than
1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with
similar low frequency (≤1.2%) in both treatment groups. Overall, clinical trial experience
showed that liver function test abnormalities observed during pravastatin therapy were
usually asymptomatic, not associated with cholestasis, and did not appear to be related to
treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic
(>6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver
disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary
safety endpoint was the proportion of subjects with at least one ALT ≥2 times the upper
limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a
doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal)
at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the
prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving
placebo. Conclusions regarding liver safety are limited since the study was not large
enough to establish similarity between groups (with 95% confidence) in the rates of ALT
elevation.
It is recommended that liver function tests be performed prior to the initiation of
therapy and when clinically indicated.
Active
liver
disease
or
unexplained
persistent
transaminase
elevations
are
contraindications to the use of pravastatin (see CONTRAINDICATIONS). Caution
should be exercised when pravastatin is administered to patients who have a recent (<6
months) history of liver disease, have signs that may suggest liver disease (e.g.,
unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol (see
CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients
should be closely monitored, started at the lower end of the recommended dosing range
(see DOSAGE AND ADMINISTRATION: Adult Patients), and titrated to the desired
therapeutic effect.
Patients who develop increased transaminase levels or signs and symptoms of active liver
disease while taking pravastatin should be evaluated with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent liver function
tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of
three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy
is recommended.
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Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria
have been reported with pravastatin and other drugs in this class. Uncomplicated
myalgia has also been reported in pravastatin-treated patients (see ADVERSE
REACTIONS). Myopathy, defined as muscle aching or muscle weakness in conjunction
with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper
limit of normal, was rare (<0.1%) in pravastatin clinical trials. Myopathy should be
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or
marked elevation of CPK. Patients should be advised to report promptly unexplained
muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Pravastatin therapy should be discontinued if markedly elevated CPK levels occur
or myopathy is diagnosed or suspected. Pravastatin therapy should also be
temporarily withheld in any patient experiencing an acute or serious condition
predisposing to the development of renal failure secondary to rhabdomyolysis, e.g.,
sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or
electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is
increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or
fibrates. However, neither myopathy nor significant increases in CPK levels have been
observed in three reports involving a total of 100 post-transplant patients (24 renal and 76
cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and
cyclosporine. Some of these patients also received other concomitant immunosuppressive
therapies. Further, in clinical trials involving small numbers of patients who were treated
concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and
gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked
CPK elevations versus one of 73 patients receiving placebo. There was a trend toward
more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms
in the group receiving combined treatment as compared with the groups receiving
placebo, gemfibrozil, or pravastatin monotherapy (see PRECAUTIONS: Drug
Interactions). The use of fibrates alone may occasionally be associated with
myopathy. The combined use of pravastatin and fibrates should be avoided unless
the benefit of further alterations in lipid levels is likely to outweigh the increased
risk of this drug combination.
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PRECAUTIONS
General
PRAVACHOL (pravastatin sodium) may elevate creatine phosphokinase and
transaminase levels (see ADVERSE REACTIONS). This should be considered in the
differential diagnosis of chest pain in a patient on therapy with pravastatin.
Homozygous Familial Hypercholesterolemia. Pravastatin has not been evaluated in
patients with rare homozygous familial hypercholesterolemia. In this group of patients, it
has been reported that HMG-CoA reductase inhibitors are less effective because the
patients lack functional LDL receptors.
Renal Insufficiency. A single 20 mg oral dose of pravastatin was administered to 24
patients with varying degrees of renal impairment (as determined by creatinine
clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-
hydroxy isomeric metabolite (SQ 31,906). A small increase was seen in mean AUC
values and half-life (t½) for the inactive enzymatic ring hydroxylation metabolite
(SQ 31,945). Given this small sample size, the dosage administered, and the degree of
individual variability, patients with renal impairment who are receiving pravastatin
should be closely monitored.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever (see WARNINGS: Skeletal
Muscle).
Drug Interactions
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See
WARNINGS: Skeletal Muscle.
Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is
not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been
shown in studies with known cytochrome P450 3A4 inhibitors (see Diltiazem and
Itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include
ketoconazole, mibefradil, and erythromycin.
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Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had
no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of
another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome
P450 3A4 increased by factors of 3.6 and 4.3, respectively.
Itraconazole: The mean AUC and Cmax for pravastatin were increased by factors of 1.7
and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which
also inhibits p-glycoprotein transport) as compared to placebo. The mean t½ was not
affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC
were due solely to increased bioavailability rather than a decrease in clearance, consistent
with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is
thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors,
including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19
and 17, respectively, when given with itraconazole.
Antipyrine: Since concomitant administration of pravastatin had no effect on the
clearance of antipyrine, interactions with other drugs metabolized via the same hepatic
cytochrome isozymes are not expected.
Cholestyramine/Colestipol: Concomitant administration resulted in an approximately
40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was
administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol
and a standard meal, there was no clinically significant decrease in bioavailability or
therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant
Therapy.)
Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant
effect on prothrombin time when administered in a study to normal elderly subjects who
were stabilized on warfarin.
Cimetidine: The AUC0-12 hr for pravastatin when given with cimetidine was not
significantly different from the AUC for pravastatin when given alone. A significant
difference was observed between the AUC’s for pravastatin when given with cimetidine
compared to when administered with antacid.
Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin
and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin
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were not affected. The AUC of pravastatin tended to increase, but the overall
bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not
altered.
Cyclosporine: Some investigators have measured cyclosporine levels in patients on
pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful
elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found
to be increased in cardiac transplant patients receiving cyclosporine.
Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant
single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary
excretion and protein binding of pravastatin. In addition, there was a significant increase
in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906. Combination therapy
with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS:
Skeletal Muscle.)
In interaction studies with aspirin, antacids (1 hour prior to PRAVACHOL), cimetidine,
nicotinic acid, or probucol, no statistically significant differences in bioavailability were
seen when PRAVACHOL (pravastatin sodium) was administered.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating
cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid
hormone production. Results of clinical trials with pravastatin in males and post-
menopausal females were inconsistent with regard to possible effects of the drug on basal
steroid hormone levels. In a study of 21 males, the mean testosterone response to human
chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment
with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change
significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors
on spermatogenesis and fertility have not been studied in adequate numbers of patients.
The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females
are unknown. Patients treated with pravastatin who display clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may diminish the levels or activity of steroid hormones.
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22
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were
treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the
adolescents aged 14-18 years) for two years, there were no detectable differences seen in
any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol
(girls) or testosterone (boys)] relative to placebo. There were no detectable differences
seen in height and weight changes, testicular volume changes, or Tanner score relative to
placebo.
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and
mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with
pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at
approximately 59 times the human dose of 80 mg/day, based on AUC. Similar CNS
vascular lesions have been observed with several other drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30
times higher than the mean drug level in humans taking the highest recommended dose
(as measured by total enzyme inhibitory activity). This same drug also produced
vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in
dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug
level similar to that seen with the 60 mg/kg/day dose.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight,
there was an increased incidence of hepatocellular carcinomas in males at the highest
dose (p<0.01). These effects in rats were observed at approximately 12 times the human
dose (HD) of 80 mg based on body surface area mg/m2 and at approximately 4 times the
human dose, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased
(p=0.013). These effects in mice were observed at approximately 15 times
(250 mg/kg/day) and 23 times (500 mg/kg/day) the human dose of 80 mg, based on
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23
AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug
exposures approximately 2 times the human dose of 80 mg, based on AUC), there were
no drug-induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of
Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/-
mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene
conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of
mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.
In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance. However, in a study with
another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated
for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a
subsequent fertility study when this same dose was administered for 11 weeks (the entire
cycle of spermatogenesis, including epididymal maturation). In rats treated with this
same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis
and loss of spermatogenic epithelium) was observed. Although not seen with pravastatin,
two similar drugs in this class caused drug-related testicular atrophy, decreased
spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The
clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X.
See CONTRAINDICATIONS.
Safety in pregnant women has not been established. Pravastatin was not teratogenic in
rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These
doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area
(mg/meter2). Rare reports of congenital anomalies have been received following
intrauterine exposure to other HMG-CoA reductase inhibitors. In a review9 of
approximately 100 prospectively followed pregnancies in women exposed to simvastatin
or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal
deaths/stillbirths did not exceed what would be expected in the general population. The
number of cases is adequate only to exclude a three-to-four-fold increase in congenital
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24
anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at
some point in the first trimester when pregnancy was identified. As safety in pregnant
women has not been established and there is no apparent benefit to therapy with
PRAVACHOL during pregnancy (see CONTRAINDICATIONS), treatment should be
immediately discontinued as soon as pregnancy is recognized. PRAVACHOL
(pravastatin sodium) should be administered to women of child-bearing potential only
when such patients are highly unlikely to conceive and have been informed of the
potential hazards.
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential
for serious adverse reactions in nursing infants, women taking PRAVACHOL should not
nurse (see CONTRAINDICATIONS).
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8-18
years of age have been evaluated in a placebo-controlled study of 2 years duration.
Patients treated with pravastatin had an adverse experience profile generally similar to
that of patients treated with placebo with influenza and headache commonly reported in
both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses
greater than 40 mg have not been studied in this population. Children and adolescent
females of childbearing potential should be counseled on appropriate contraceptive
methods
while
on
pravastatin
therapy
(see
CONTRAINDICATIONS
and
PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND
ADMINISTRATION: Adult Patients and Pediatric Patients.
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age
have not been conducted.
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of
6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across
these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were
aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing
cardiovascular events and in modifying lipid profiles was similar to that seen in younger
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25
subjects. The adverse event profile in the elderly was similar to that in the overall
population. Other reported clinical experience has not identified differences in responses
to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy
young subjects, but mean Cmax, Tmax and t½ values are similar in both age groups and
substantial accumulation of pravastatin would not be expected in the elderly (see
CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism).
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and
transient. In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients
and 1.2% of placebo-treated patients were discontinued from treatment because of
adverse experiences attributed to study drug therapy; this difference was not statistically
significant. (See also PRECAUTIONS: Geriatric Use.)
Adverse Clinical Events
Short-Term Controlled Trials
All adverse clinical events (regardless of attribution) reported in more than 2% of
pravastatin-treated patients in placebo-controlled trials of up to four months duration are
identified in Table 8; also shown are the percentages of patients in whom these medical
events were believed to be related or possibly related to the drug:
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26
Table 8:
Adverse Events in >2 Percent of Patients Treated with
Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials
All Events
Events Attributed
to Study Drug
Body System/Event
Pravastatin
(N=900)
% of patients
Placebo
(N=411)
% of patients
Pravastatin
(N=900)
% of patients
Placebo
(N=411)
% of patients
Cardiovascular
Cardiac Chest Pain
4.0
3.4
0.1
0.0
Dermatologic
Rash
4.0*
1.1
1.3
0.9
Gastrointestinal
Nausea/Vomiting
Diarrhea
Abdominal Pain
Constipation
Flatulence
Heartburn
7.3
6.2
5.4
4.0
3.3
2.9
7.1
5.6
6.9
7.1
3.6
1.9
2.9
2.0
2.0
2.4
2.7
2.0
3.4
1.9
3.9
5.1
3.4
0.7
General
Fatigue
Chest Pain
Influenza
3.8
3.7
2.4*
3.4
1.9
0.7
1.9
0.3
0.0
1.0
0.2
0.0
Musculoskeletal
Localized Pain
Myalgia
10.0
2.7
9.0
1.0
1.4
0.6
1.5
0.0
Nervous System
Headache
Dizziness
6.2
3.3
3.9
3.2
1.7*
1.0
0.2
0.5
Renal/Genitourinary
Urinary Abnormality
2.4
2.9
0.7
1.2
Respiratory
Common Cold
Rhinitis
Cough
7.0
4.0
2.6
6.3
4.1
1.7
0.0
0.1
0.1
0.0
0.0
0.0
*Statistically significantly different from placebo.
The safety and tolerability of PRAVACHOL at a dose of 80 mg in two controlled trials
with a mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses
except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of
CK >10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.
Long-Term Controlled Morbidity and Mortality Trials
Adverse event data were pooled from seven double-blind, placebo-controlled trials (West
of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study
[CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID];
Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I];
Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression
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27
Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention
Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and
10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin
group was comparable to that of the placebo group. Patients were exposed to pravastatin
for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I,
PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for
discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these
seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to
be of probable, possible, or uncertain relationship to study drug, occurring in at least 1%
of patients treated with pravastatin in these studies are identified in Table 9.
Table 9:
Adverse Events in ≥1 Percent of Patients Treated with Pravastatin
40 mg in Long-Term Placebo-Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Cardiovascular
Angina Pectoris
3.1
3.4
Dermatologic
Rash
2.1
2.2
Gastrointestinal
Dyspepsia/Heartburn
Abdominal Pain
Nausea/Vomiting
Flatulence
Constipation
3.5
2.4
1.6
1.2
1.2
3.7
2.5
1.6
1.1
1.3
General
Fatigue
Chest Pain
3.4
2.6
3.3
2.6
Musculoskeletal
Musculoskeletal Pain (includes arthralgia)
Muscle Cramp
Myalgia
6.0
2.0
1.4
5.8
1.8
1.4
Nervous System
Dizziness
Headache
Sleep Disturbance
Depression
Anxiety/Nervousness
2.2
1.9
1.0
1.0
1.0
2.1
1.8
0.9
1.0
1.2
Renal/Genitourinary
Urinary Abnormality (includes dysuria, frequency, nocturia)
1.0
0.8
Respiratory
Dyspnea
Upper Respiratory Infection
Cough
1.6
1.3
1.0
1.6
1.3
1.0
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
1.6
1.3
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Events of probable, possible, or uncertain relationship to study drug that occurred in
<1.0% of pravastatin-treated patients in the long-term trials included the following;
frequencies were similar in placebo-treated patients:
Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including
alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
Gastrointestinal: decreased appetite.
General: fever, flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy
(including peripheral neuropathy).
Special Senses: lens opacity, taste disturbance.
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following
events have been reported rarely during postmarketing experience with PRAVACHOL,
regardless of causality assessment:
Musculoskeletal: myopathy, rhabdomyolysis.
Nervous System: dysfunction of certain cranial nerves (including alteration of taste,
impairment of extraocular movement, facial paresis), peripheral nerve palsy.
Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome,
polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia,
positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills,
malaise, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson
syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic
jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma.
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Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Reproductive: gynecomastia.
Laboratory Abnormalities: Liver Function Test abnormalities, thyroid function
abnormalities.
Laboratory Test Abnormalities
Increases in serum transaminase (ALT, AST) values and CPK have been observed (see
WARNINGS).
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually
returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia
have been reported with HMG-CoA reductase inhibitors.
Concomitant Therapy
Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic
acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either
probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with
greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin
alone. No adverse reactions unique to the combination or in addition to those previously
reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or
without acute renal failure) have been reported when another HMG-CoA reductase
inhibitor was used in combination with immunosuppressive drugs, gemfibrozil,
erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-
CoA reductase inhibitors and these agents is generally not recommended. (See
WARNINGS: Skeletal Muscle and PRECAUTIONS: Drug Interactions.)
Pediatric Patients
In a two-year, double-blind, placebo-controlled study involving 100 boys and 114 girls
with HeFH, the safety and tolerability profile of pravastatin was generally similar to that
of placebo. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Study and
PRECAUTIONS: Pediatric Use.)
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OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose
occurs, it should be treated symptomatically with laboratory monitoring and supportive
measures should be instituted as required. (See WARNINGS.)
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL (pravastatin sodium) and should continue on this diet during treatment
with PRAVACHOL (see NCEP Treatment Guidelines for details on dietary therapy).
PRAVACHOL can be administered orally as a single dose at any time of the day, with or
without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic
lipid determinations should be performed at this time and dosage adjusted according to
the patient’s response to therapy and established treatment guidelines.
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not
achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a
history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is
recommended.
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses
greater than 20 mg have not been studied in this patient population.
Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age.
Doses greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be reevaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C (see INDICATIONS AND USAGE: Hyperlipidemia, NCEP Treatment
Guidelines).
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In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS:
Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of
pravastatin sodium once-a-day at bedtime and titration to higher doses should be done
with caution. Most patients treated with this combination received a maximum
pravastatin sodium dose of 20 mg/day.
Concomitant Therapy
The lipid-lowering effects of PRAVACHOL on Total- and LDL-cholesterol are enhanced
when combined with a bile-acid-binding resin. When administering a bile-acid-binding
resin (e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given
either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE
REACTIONS: Concomitant Therapy.)
HOW SUPPLIED
PRAVACHOL® (pravastatin sodium) Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P”
embossed on one side and “PRAVACHOL 10” engraved on the opposite side. They are
supplied in bottles of 90 (NDC 0003-5154-05). Bottles contain a desiccant canister.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 20” engraved on the opposite side. They are supplied in
bottles of 90 (NDC 0003-5178-05) and bottles of 1000 (NDC 0003-5178-75). Bottles
contain a desiccant canister.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 40” engraved on the opposite side. They are supplied in
bottles of 90 (NDC 0003-5194-10). Bottles contain a desiccant canister.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other
side. They are supplied in bottles of 90 (NDC 0003-5195-10). Bottles contain a desiccant
canister.
STORAGE
Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F) [see USP
Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect
from light.
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32
REFERENCES
1 Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in Men with
Hypercholesterolemia (WOS). N Engl J Med 1995;333:1301-7.
2 The Long-term Intervention with Pravastatin in Ischemic Disease Group. Prevention
of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart
Disease and a Broad Range of Initial Cholesterol Levels (LIPID). N Engl J Med
1998;339:1349-1357.
3 Sacks FM, et al. The Effect of Pravastatin on Coronary Events After Myocardial
Infarction in Patients with Average Cholesterol Levels (CARE). N Engl J Med
1996;335:1001-9.
4 Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries
(PLAC I): Reduction in Atherosclerosis Progression and Clinical Events. J Am Coll
Cardiol 1995;26:1133-9.
5 Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression and
Regression of Coronary Artery Disease in Symptomatic Man With Normal to
Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation
Statin Study (REGRESS). Circulation 1995;91:2528-2540.
6 Crouse JR, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries:
Design Features of a Clinical Trial with Carotid Atherosclerosis Outcome (PLAC II).
Controlled Clinical Trials 1992;13:495.
7 Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A Population-
based Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic
Progression in Carotid and Femoral Arteries. Research Institute of Public Health,
University of Kuopio, Finland. Circulation 1995;92:1758.
8 Fredrickson DS, et al. Fat Transport in Lipoproteins-An Integrated Approach to
Mechanisms and Disorders. N Engl J Med 1967;276:34-42, 94-102, 148-156, 215-
224, 273-281.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
33
9 Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing
Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive
Toxicology 1996;10(6):439-446.
US Patent Nos.: 4,346,227; 5,030,447; 5,180,589; 5,622,985
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Revised TBD
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|
custom-source
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2025-02-12T13:46:15.446734
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRAVACHOL safely and effectively. See full prescribing information for
PRAVACHOL.
PRAVACHOL (pravastatin sodium) Tablets
Initial U.S. Approval: 1991
---------------------------INDICATIONS AND USAGE---------------------------
PRAVACHOL is an HMG-CoA reductase inhibitor (statin) indicated as an
adjunctive therapy to diet to:
Reduce the risk of MI, revascularization, and cardiovascular mortality in
hypercholesterolemic patients without clinically evident CHD. (1.1)
Reduce the risk of total mortality by reducing coronary death, MI,
revascularization,
stroke/TIA,
and
the
progression
of
coronary
atherosclerosis in patients with clinically evident CHD. (1.1)
Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase
HDL-C in patients with primary hypercholesterolemia and mixed
dyslipidemia. (1.2)
Reduce elevated serum TG levels in patients with hypertriglyceridemia.
(1.2)
Treat patients with primary dysbetalipoproteinemia who are not responding
to diet. (1.2)
Treat children and adolescent patients ages 8 years and older with
heterozygous familial hypercholesterolemia after failing an adequate trial
of diet therapy. (1.2)
Limitations of use:
PRAVACHOL has not been studied in Fredrickson Types I and V
dyslipidemias. (1.3)
------------------------DOSAGE AND ADMINISTRATION---------------------
Adults: the recommended starting dose is 40 mg once daily. Use 80 mg
dose only for patients not reaching LDL-C goal with 40 mg. (2.2)
Significant renal impairment: the recommended starting dose is 10 mg once
daily. (2.2)
Children (ages 8 to 13 years, inclusive): the recommended starting dose is
20 mg once daily. (2.3)
Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg
once daily. (2.3)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
Tablets: 10 mg, 20 mg, 40 mg, 80 mg. (3)
------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to any component of this medication. (4.1, 6.2, 11)
Active liver disease or unexplained, persistent elevations of serum
transaminases. (4.2, 5.2)
Women who are pregnant or may become pregnant. (4.3, 8.1)
Nursing mothers. (4.4, 8.3)
------------------------WARNINGS AND PRECAUTIONS----------------------
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing
factors include advanced age (>65), uncontrolled hypothyroidism, and
renal impairment. Patients should be advised to report promptly any
symptoms of myopathy. Pravastatin therapy should be discontinued if
myopathy is diagnosed or suspected. (5.1)
Liver enzyme abnormalities and monitoring: persistent elevations in
hepatic transaminase can occur. Monitor liver enzymes before and during
treatment. (5.2)
-------------------------------ADVERSE REACTIONS-----------------------------
In short-term clinical trials, the most commonly reported adverse reactions (≥2%
and > placebo) regardless of causality were: musculoskeletal pain,
nausea/vomiting, upper respiratory infection, diarrhea, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS----------------------------
Fibrates: use with fibrate products may increase the risk of adverse skeletal
muscle effects. (2.4, 5.1)
Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg
once daily. (2.5, 7.1)
Clarithromycin: combination increases exposure. Limit pravastatin to
40 mg once daily. (2.6, 7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 05/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
8.1
Pregnancy
1.1
Prevention of Cardiovascular Disease
8.3
Nursing Mothers
1.2
Hyperlipidemia
8.4
Pediatric Use
1.3
Limitations of Use
8.5
Geriatric Use
2
DOSAGE AND ADMINISTRATION
8.6
Homozygous Familial Hypercholesterolemia
2.1
General Dosing Information
10
OVERDOSAGE
2.2
Adult Patients
11
DESCRIPTION
2.3
Pediatric Patients
12
CLINICAL PHARMACOLOGY
2.4
Concomitant Lipid-Altering Therapy
12.1
Mechanism of Action
2.5
Dosage in Patients Taking Cyclosporine
12.2
Pharmacokinetics
2.6
Dosage in Patients Taking Clarithromycin
13
NONCLINICAL TOXICOLOGY
3
DOSAGE FORMS AND STRENGTHS
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
4
CONTRAINDICATIONS
13.2
Animal Toxicology and/or Pharmacology
4.1
Hypersensitivity
14
CLINICAL STUDIES
4.2
Liver
14.1
Prevention of Coronary Heart Disease
4.3
Pregnancy
14.2
Secondary Prevention of Cardiovascular Events
4.4
Nursing Mothers
14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and
5
WARNINGS AND PRECAUTIONS
IIb)
5.1
Skeletal Muscle
14.4
Hypertriglyceridemia (Fredrickson Type IV)
5.2
Liver
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
5.3
Endocrine Function
14.6
Pediatric Clinical Study
6
ADVERSE REACTIONS
15
REFERENCES
6.1
Adverse Clinical Events
16
HOW SUPPLIED/STORAGE AND HANDLING
6.2
Postmarketing Experience
16.1
How Supplied
6.3
Laboratory Test Abnormalities
16.2
Storage
6.4
Pediatric Patients
17
PATIENT COUNSELING INFORMATION
7
DRUG INTERACTIONS
7.1
Cyclosporine
* Sections or subsections omitted from the full prescribing information
7.2
Clarithromycin
are not listed.
8
USE IN SPECIFIC POPULATIONS
1
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor
intervention in individuals at significantly increased risk for atherosclerotic vascular disease due
to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a
diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has
been inadequate.
1.1
Prevention of Cardiovascular Disease
In hypercholesterolemic patients without clinically evident coronary heart disease (CHD),
PRAVACHOL (pravastatin sodium) is indicated to:
reduce the risk of myocardial infarction (MI).
reduce the risk of undergoing myocardial revascularization procedures.
reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular
causes.
In patients with clinically evident CHD, PRAVACHOL is indicated to:
reduce the risk of total mortality by reducing coronary death.
reduce the risk of MI.
reduce the risk of undergoing myocardial revascularization procedures.
reduce the risk of stroke and stroke/transient ischemic attack (TIA).
slow the progression of coronary atherosclerosis.
1.2
Hyperlipidemia
PRAVACHOL is indicated:
as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase
high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia
and mixed dyslipidemia (Fredrickson Types IIa and IIb).1
as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson
Type IV).
for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III)
who do not respond adequately to diet.
2
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
as an adjunct to diet and lifestyle modification for treatment of heterozygous familial
hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if
after an adequate trial of diet the following findings are present:
a. LDL-C remains ≥190 mg/dL or
b. LDL-C remains ≥160 mg/dL and:
there is a positive family history of premature cardiovascular disease (CVD) or
two or more other CVD risk factors are present in the patient.
1.3
Limitations of Use
PRAVACHOL has not been studied in conditions where the major lipoprotein abnormality is
elevation of chylomicrons (Fredrickson Types I and V).
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL and should continue on this diet during treatment with PRAVACHOL [see
NCEP Treatment Guidelines for details on dietary therapy].
2.2
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve
desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal
impairment, a starting dose of 10 mg daily is recommended. PRAVACHOL can be administered
orally as a single dose at any time of the day, with or without food. Since the maximal effect of a
given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time
and dosage adjusted according to the patient’s response to therapy and established treatment
guidelines.
2.3
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than
20 mg have not been studied in this patient population.
3
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses
greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be reevaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C [see Indications and Usage (1.2)].
2.4
Concomitant Lipid-Altering Therapy
PRAVACHOL may be used with bile acid resins. When administering a bile-acid-binding resin
(e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given either 1 hour
or more before or at least 4 hours following the resin. [See Clinical Pharmacology (12.3).]
The combination of statins and fibrates should generally be used with caution. [See Warnings
and Precautions (5.1).]
2.5
Dosage in Patients Taking Cyclosporine
In patients taking immunosuppressive drugs such as cyclosporine concomitantly with
pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and
titration to higher doses should be done with caution. Most patients treated with this combination
received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine,
therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and
Precautions (5.1) and Drug Interactions (7.1)].
2.6
Dosage in Patients Taking Clarithromycin
In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once
daily [see Drug Interactions (7.2)].
3
DOSAGE FORMS AND STRENGTHS
PRAVACHOL Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 10” engraved on the opposite side.
4
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
4
CONTRAINDICATIONS
4.1
Hypersensitivity
Hypersensitivity to any component of this medication.
4.2
Liver
Active liver disease or unexplained, persistent elevations of serum transaminases [see Warnings
and Precautions (5.2)].
4.3
Pregnancy
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
components for fetal development (including synthesis of steroids and cell membranes). Since
statins decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in nursing
mothers.
PRAVASTATIN
SHOULD
BE
ADMINISTERED
TO
WOMEN
OF
CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO
CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient
becomes pregnant while taking this class of drug, therapy should be discontinued immediately
and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations
(8.1)].
5
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4.4
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because statins have the
potential for serious adverse reactions in nursing infants, women who require PRAVACHOL
treatment should not breast-feed their infants [see Use in Specific Populations (8.3)].
5
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have
been reported with pravastatin and other drugs in this class. A history of renal impairment
may be a risk factor for the development of rhabdomyolysis. Such patients merit closer
monitoring for skeletal muscle effects.
Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse
Reactions (6)]. Myopathy, defined as muscle aching or muscle weakness in conjunction with
increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of
normal (ULN), was rare (<0.1%) in pravastatin clinical trials. Myopathy should be considered in
any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of
CPK. Predisposing factors include advanced age (>65), uncontrolled hypothyroidism, and renal
impairment. Patients should be advised to report promptly unexplained muscle pain, tenderness,
or weakness, particularly if accompanied by malaise or fever. Pravastatin therapy should be
discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Pravastatin therapy should also be temporarily withheld in any patient experiencing an
acute or serious condition predisposing to the development of renal failure secondary to
rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic,
endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy during treatment with statins is increased with concurrent therapy with
either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant
increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant
patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to
40 mg and cyclosporine. Some of these patients also received other concomitant
immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who
were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil
6
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations
versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK
elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving
combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin
monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The
benefit of further alterations in lipid levels by the combined use of PRAVACHOL with
fibrates should be carefully weighed against the potential risks of this combination.
5.2
Liver
Statins, like some other lipid-lowering therapies, have been associated with biochemical
abnormalities of liver function. In 3 long-term (4.8-5.9 years), placebo-controlled clinical trials
(WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or
placebo [see Clinical Studies (14)]. In an analysis of serum transaminase values (ALT, AST),
incidences of marked abnormalities were compared between the pravastatin and placebo
treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3
times the upper limit of normal for subjects with pretreatment values less than or equal to the
upper limit of normal, or 4 times the pretreatment value for subjects with pretreatment values
greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked
abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment
groups. Overall, clinical trial experience showed that liver function test abnormalities observed
during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did
not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial,
subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or non
alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months.
The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the
upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a
doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at
baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the
prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo.
Conclusions regarding liver safety are limited since the study was not large enough to establish
similarity between groups (with 95% confidence) in the rates of ALT elevation.
It is recommended that liver function tests be performed prior to the initiation of therapy
and when clinically indicated.
7
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active liver disease or unexplained persistent transaminase elevations are contraindications to
the use of pravastatin [see Contraindications (4.2)]. Caution should be exercised when
pravastatin is administered to patients who have a recent (<6 months) history of liver disease,
have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations,
jaundice), or are heavy users of alcohol.
Patients who develop increased transaminase levels or signs and symptoms of active liver
disease while taking pravastatin should be evaluated with a second liver function evaluation to
confirm the finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) returns to normal. Should an increase in AST or ALT of 3 times the upper limit
of normal or greater persist, withdrawal of pravastatin therapy is recommended.
5.3
Endocrine Function
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such,
might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials
with pravastatin in males and post-menopausal females were inconsistent with regard to possible
effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone
response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of
treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change significantly
after therapy in these patients. The effects of statins on spermatogenesis and fertility have not
been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-
gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who
display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution
should also be exercised if a statin or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may
diminish the levels or activity of steroid hormones.
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated
with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18
years) for 2 years, there were no detectable differences seen in any of the endocrine parameters
(ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to
placebo. There were no detectable differences seen in height and weight changes, testicular
volume changes, or Tanner score relative to placebo.
8
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In
4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of
placebo-treated patients were discontinued from treatment because of adverse experiences
attributed to study drug therapy; this difference was not statistically significant.
6.1
Adverse Clinical Events
Short-Term Controlled Trials
In the PRAVACHOL placebo-controlled clinical trials database of 1313 patients (age range
20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2%
Others) with a median treatment duration of 14 weeks, 3.3% of patients on PRAVACHOL and
1.2% patients on placebo discontinued due to adverse events regardless of causality. The most
common adverse reactions that led to treatment discontinuation and occurred at an incidence
greater than placebo were: liver function test increased, nausea, anxiety/depression, and
dizziness.
All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated
patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:
Table 1:
Adverse Events in 2% of Patients Treated with Pravastatin 5 to
40 mg and at an Incidence Greater Than Placebo in Short-Term
Placebo-Controlled Trials (% of patients)
Body System/Event
5 mg
N=100
10 mg
N=153
20 mg
N=478
40 mg
N=171
Any Dose
N=902
Placebo
N=411
Cardiovascular
Angina Pectoris
5.0
4.6
4.8
3.5
4.5
3.4
Dermatologic
Rash
3.0
2.6
6.7
1.2
4.5
1.4
Gastrointestinal
Nausea/Vomiting
Diarrhea
Flatulence
Dyspepsia/Heartburn
Abdominal Distension
4.0
8.0
2.0
0.0
2.0
5.9
8.5
3.3
3.3
3.3
10.5
6.5
4.6
3.6
2.1
2.3
4.7
0.0
0.6
0.6
7.4
6.7
3.2
2.5
2.0
7.1
5.6
4.4
2.7
2.4
General
4.0
1.3
5.2
0.0
3.4
3.9
Fatigue
4.0
1.3
3.3
1.2
2.7
1.9
9
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Adverse Events in 2% of Patients Treated with Pravastatin 5 to
40 mg and at an Incidence Greater Than Placebo in Short-Term
Placebo-Controlled Trials (% of patients)
Body System/Event
5 mg
N=100
10 mg
N=153
20 mg
N=478
40 mg
N=171
Any Dose
N=902
Placebo
N=411
Chest Pain
Influenza
4.0
2.6
1.9
0.6
2.0
0.7
Musculoskeletal
Musculoskeletal Pain
13.0
3.9
13.2
5.3
10.1
10.2
Myalgia
1.0
2.6
2.9
1.2
2.3
1.2
Nervous System
Headache
Dizziness
5.0
4.0
6.5
1.3
7.5
5.2
3.5
0.6
6.3
3.5
4.6
3.4
Respiratory
Pharyngitis
Upper Respiratory Infection
Rhinitis
Cough
2.0
6.0
7.0
4.0
4.6
9.8
5.2
1.3
1.5
5.2
3.8
3.1
1.2
4.1
1.2
1.2
2.0
5.9
3.9
2.5
2.7
5.8
4.9
1.7
Investigation
ALT Increased
g-GT Increased
CPK Increased
2.0
3.0
5.0
2.0
2.6
1.3
4.0
2.1
5.2
1.2
0.6
2.9
2.9
2.0
4.1
1.2
1.2
3.6
The safety and tolerability of PRAVACHOL at a dose of 80 mg in 2 controlled trials with a
mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses except that 4
out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN
compared to 0 out of 115 patients taking 40 mg of pravastatin.
Long-Term Controlled Morbidity and Mortality Trials
In the PRAVACHOL placebo-controlled clinical trials database of 21,483 patients (age range
24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians,
0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of
patients on PRAVACHOL and 9.3% patients on placebo discontinued due to adverse events
regardless of causality.
Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland
Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term
Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of
Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis
10
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and
Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated
with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability
profile in the pravastatin group was comparable to that of the placebo group. Patients were
exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9
years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common
reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively,
these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse
events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these
studies are identified in Table 2.
Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Dermatologic
Rash (including dermatitis)
7.2
7.1
General
Edema
3.0
2.7
Fatigue
8.4
7.8
Chest Pain
10.0
9.8
Fever
2.1
1.9
Weight Gain
3.8
3.3
Weight Loss
3.3
2.8
Musculoskeletal
Musculoskeletal Pain
24.9
24.4
Muscle Cramp
5.1
4.6
Musculoskeletal Traumatism
10.2
9.6
Nervous System
Dizziness
7.3
6.6
Sleep Disturbance
3.0
2.4
Anxiety/Nervousness
4.8
4.7
Paresthesia
3.2
3.0
Renal/Genitourinary
Urinary Tract Infection
2.7
2.6
Respiratory
Upper Respiratory Tract Infection
21.2
20.2
Cough
8.2
7.4
Influenza
9.2
9.0
Pulmonary Infection
3.8
3.5
11
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Sinus Abnormality
Tracheobronchitis
7.0
3.4
6.7
3.1
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
3.4
3.3
Infections
Viral Infection
3.2
2.9
In addition to the events listed above in the long-term trials table, events of probable, possible, or
uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the
long-term trials included the following:
Dermatologic: scalp hair abnormality (including alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
General: flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral
neuropathy).
Special Senses: taste disturbance.
6.2
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following events
have been reported rarely during postmarketing experience with PRAVACHOL, regardless of
causality assessment:
Musculoskeletal: myopathy, rhabdomyolysis.
12
Reference ID: 2948362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment
of extraocular movement, facial paresis), peripheral nerve palsy.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These
cognitive issues have been reported for all statins. The reports are generally nonserious, and
reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and
symptom resolution (median of 3 weeks).
Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR
increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal
necrolysis, erythema multiforme (including Stevens-Johnson syndrome).
Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active
hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis,
hepatoma.
Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Renal: urinary abnormality (including dysuria, frequency, nocturia).
Respiratory: dyspnea.
Reproductive: gynecomastia.
Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.
6.3
Laboratory Test Abnormalities
Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions
(5.1, 5.2)].
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to
normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been
reported with statins.
13
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6.4
Pediatric Patients
In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH
(n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1%
Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.
[See Warnings and Precautions (5.3), Use in Specific Populations (8.4), and Clinical
Pharmacology (12.3).]
7
DRUG INTERACTIONS
For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or
erythromycin, the risk of myopathy increases [see Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
7.1
Cyclosporine
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see
Dosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology
(12.3)].
7.2
Clarithromycin
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin
[see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical
Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category X
[See Contraindications (4.3).]
14
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Safety in pregnant women has not been established. Available data in women inadvertently
taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are
no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether
pravastatin can cause fetal harm when administered to a pregnant woman or can affect
reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit
outweighs the potential risk to the fetus and patients have been informed of the potential hazards.
Rare reports of congenital anomalies have been received following intrauterine exposure to other
statins. In a review2 of approximately 100 prospectively followed pregnancies in women
exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous
abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate to exclude a ≥3- to 4-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed pregnancies,
drug treatment was initiated prior to pregnancy and was discontinued at some point in the first
trimester when pregnancy was identified. As safety in pregnant women has not been established
and there is no apparent benefit to therapy with PRAVACHOL during pregnancy [see
Contraindications (4.3)], treatment should be immediately discontinued as soon as pregnancy is
recognized. PRAVACHOL should be administered to women of childbearing potential only
when such patients are highly unlikely to conceive and have been informed of the potential
hazards.
Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in
rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times
(rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on
surface area (mg/m2).
In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation
days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were
observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day
MRHD based on body surface area (mg/m2).
In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17
through lactation day 21 (weaning) increased mortality of offspring and developmental delays
were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day
MRHD based on body surface area (mg/m2).
15
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8.3
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential for
serious adverse reactions in nursing infants, women taking PRAVACHOL should not nurse [see
Contraindications (4.4)].
Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels
following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in
lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels
than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.
8.4
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8 to 18 years of
age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with
pravastatin had an adverse experience profile generally similar to that of patients treated with
placebo with influenza and headache commonly reported in both treatment groups. [See Adverse
Reactions (6.4).] Doses greater than 40 mg have not been studied in this population.
Children and adolescent females of childbearing potential should be counseled on appropriate
contraceptive methods while on pravastatin therapy [see Contraindications (4.3) and Use in
Specific Populations (8.1)]. For dosing information [see Dosage and Administration (2.3).]
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not
been conducted.
8.5
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593
subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies,
36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The
beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in
modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in
the elderly was similar to that in the overall population. Other reported clinical experience has
not identified differences in responses to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25%-50%) higher in elderly subjects than in healthy young
subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma
16
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concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial
accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology
(12.3)].
Since advanced age (≥65 years) is a predisposing factor for myopathy, PRAVACHOL should be
prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
8.6
Homozygous Familial Hypercholesterolemia
Pravastatin
has
not
been
evaluated
in
patients
with
rare
homozygous
familial
hypercholesterolemia. In this group of patients, it has been reported that statins are less effective
because the patients lack functional LDL receptors.
10
OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs,
it should be treated symptomatically with laboratory monitoring and supportive measures should
be instituted as required.
11
DESCRIPTION
PRAVACHOL (pravastatin sodium) is one of a class of lipid-lowering compounds, the statins,
which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a
hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium
salt,
[1S
[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.
Structural formula:
17
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structural formula
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively
polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It
is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically
insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg tablets.
Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide, magnesium
stearate, microcrystalline cellulose, and povidone. The 10 mg tablet also contains Red Ferric
Oxide, the 20 mg and 80 mg tablets also contain Yellow Ferric Oxide, and the 40 mg tablet also
contains Green Lake Blend (mixture of D&C Yellow No. 10-Aluminum Lake and FD&C Blue
No. 1-Aluminum Lake).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces
VLDL and TG and increases HDL-C.
18
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12.2
Pharmacokinetics
General
Absorption: PRAVACHOL is administered orally in the active form. In studies in man, peak
plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on
urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and
absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or
1 hour prior to meals.
Pravastatin plasma concentrations, including area under the concentration-time curve (AUC),
Cmax, and steady-state minimum (Cmin), are directly proportional to administered dose. Systemic
bioavailability of pravastatin administered following a bedtime dose was decreased 60%
compared to that following an AM dose. Despite this decrease in systemic bioavailability, the
efficacy of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose.
The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. The geometric means of pravastatin Cmax and AUC following a 20 mg dose in the fasted
state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.
Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin
accumulation following once or twice daily administration of PRAVACHOL tablets.
Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.
Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to 6
epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring
hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40
the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes
extensive first-pass extraction in the liver (extraction ratio 0.66).
Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the
feces. After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes
(i.e., biliary excretion and biotransformation).
19
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Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for
pravastatin is 1.8 hours in humans.
Specific Populations
Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients
with varying degrees of renal impairment (as determined by creatinine clearance). No effect was
observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite
(SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal
impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour
shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).
Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy
confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for
cirrhotic patients compared to 6-fold for healthy subjects. [See Warnings and Precautions (5.2).]
Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin
was approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65-75 years old) compared with younger men (19-31
years old). In a similar study conducted in women, the mean AUC for pravastatin was
approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65
78 years old) compared with younger women (18-38 years old). In both studies, Cmax, Tmax, and
t½ values were similar in older and younger subjects. [See Use in Specific Populations (8.5).]
Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric
means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for Cmax
were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No
conclusion can be made based on these findings due to the small number of samples and large
variability. [See Use in Specific Populations (8.4).]
20
Reference ID: 2948362
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Drug-Drug Interactions
Table 3:
Effect of Coadministered Drugs on the Pharmacokinetics of
Pravastatin
Coadministered Drug and Dosing
Regimen
Pravastatin
Dose (mg)
Change in AUC
Change in Cmax
Cyclosporine 5 mg/kg single dose
40 mg single dose
282%
327%
Clarithromycin 500 mg BID for 9 days
40 mg OD for 8 days
110%
128%
Colestipol 10 g single dose
20 mg single dose
47%
53%
Cholestyramine 4 g single dose
Administered simultaneously
Administered 1 hour apart
Administered 4 hours apart
20 mg single dose
40%
12%
12%
39%
30%
6.8%
Cholestyramine 24 g OD for 4 weeks
20 mg BID for 8 weeks
5 mg BID for 8 weeks
10 mg BID for 8 weeks
51%
38%
18%
4.9%
23%
33%
Fluconazole
200 mg IV for 6 days
200 mg PO for 6 days
20 mg PO+10 mg IV
20 mg PO+10 mg IV
34%
16%
33%
16%
Verapamil IR 120 mg for 1 day and
Verapamil ER 480 mg for 3 days
40 mg single dose
31%
42%
Cimetidine 300 mg QID for 3 days
20 mg single dose
30%
9.8%
Antacids 15 mL QID for 3 days
20 mg single dose
28%
24%
Digoxin 0.2 mg OD for 9 days
20 mg OD for 9 days
23%
26%
Probucol 500 mg single dose
20 mg single dose
14%
24%
Warfarin 5 mg OD for 6 days
20 mg BID for 6 days
13%
6.7%
Itraconazole 200 mg OD for 30 days
40 mg OD for 30 days
11% (compared to
Day 1)
17% (compared
to Day 1)
Gemfibrozil 600 mg single dose
20 mg single dose
7.0%
20%
Aspirin 324 mg single dose
20 mg single dose
4.7%
8.9%
Nicotinic Acid 1 g single dose
20 mg single dose
3.6%
8.2%
Diltiazem
20 mg single dose
2.7%
30%
Grapefruit juice
40 mg single dose
1.8%
3.7%
BID = twice daily; OD = once daily; QID = four times daily
21
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Table 4:
Effect of Pravastatin on the Pharmacokinetics of Coadministered
Drugs
Pravastatin Dosing
Regimen
Name and Dose
Change in AUC
Change in Cmax
20 mg BID for 6 days
Warfarin 5 mg OD for 6 days
Chain in mean prothrombin time
17%
0.4 sec
15%
20 mg OD for 9 days
Digoxin 0.2 mg OD for 9 days
4.6%
5.3%
20 mg BID for 4 weeks
10 mg BID for 4 weeks
5 mg BID for 4 weeks
Antipyrine 1.2 g single dose
3.0%
1.6%
Less than 1%
Not Reported
BID = twice daily; OD = once daily
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was
an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These
effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on
body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013).
These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times
(500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up
to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on
AUC), there were no drug-induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella
typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma
cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using
Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a
dominant lethal test in mice or a micronucleus test in mice.
In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance.
22
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13.2
Animal Toxicology and/or Pharmacology
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear
cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of
25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of
80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other
drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion
starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher
than the mean drug level in humans taking the highest recommended dose (as measured by total
enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at
180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the
60 mg/kg/day dose.
When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5-45 mg/kg/day), no
drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-
weight gain was observed during the dosing and 52-day recovery periods as well as slight
thinning of the corpus callosum at the end of the recovery period. This finding was not evident in
rats examined at the completion of the dosing period and was not associated with any
inflammatory or degenerative changes in the brain. The biological relevance of the corpus
callosum finding is uncertain due to the absence of any other microscopic changes in the brain or
peripheral nervous tissue and because it occurred at the end of the recovery period.
Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-
maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day
during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are
approximately 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus
callosum was observed in rats dosed with pravastatin (250 mg/kg/day) beginning PND 35 for 3
months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately
equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the
40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.
23
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14
CLINICAL STUDIES
14.1
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (WOS),3 the effect of PRAVACHOL on fatal and
nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with
LDL-C levels between 156 to 254 mg/dL (4-6.7 mmol/L). In this randomized, double-blind,
placebo-controlled study, patients were treated with standard care, including dietary advice, and
either PRAVACHOL 40 mg daily (N=3302) or placebo (N=3293) and followed for a median
duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6
months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7),
−27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either CHD death or
nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus
174 events in the PRAVACHOL group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure
below]). The risk reduction with PRAVACHOL was similar and significant throughout the entire
range of baseline LDL cholesterol levels. This reduction was also similar and significant across
the age range studied with a 40% risk reduction for patients younger than 55 years and a 27%
risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included
only men, and therefore it is not clear to what extent these data can be extrapolated to a similar
population of female patients. graph
24
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PRAVACHOL also significantly decreased the risk for undergoing myocardial revascularization
procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary
angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31%
(128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and
there was no increase in death from non-cardiovascular causes.
14.2
Secondary Prevention of Cardiovascular Events
In the LIPID4 study, the effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients
(7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris
(3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind,
placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at
randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46
and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and
HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving
aspirin and 76% were receiving antihypertensive medication. Treatment with PRAVACHOL
significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The
risk reduction due to treatment with PRAVACHOL on CHD mortality was consistent regardless
of age. PRAVACHOL significantly reduced the risk for total mortality (by reducing CHD death)
and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of
either MI or hospitalization for unstable angina pectoris.
Table 5:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=4512)
Placebo
(N=4502)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or nonfatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
25
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Table 5:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=4512)
Placebo
(N=4502)
Risk
Reduction
p-value
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the CARE5 study, the effect of PRAVACHOL, 40 mg daily, on CHD death and nonfatal MI
was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the
preceding 3 to 20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled
study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL.
LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At
baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive
medications. Median (25th, 75th percentile) percent changes from baseline after 6 months
of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4
(−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with
PRAVACHOL significantly reduced the rate of first recurrent coronary events (either CHD
death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and
the risk for stroke or TIA (see Table 6).
Table 6:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=2081)
Placebo
(N=2078)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality or nonfatal MIa
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
<0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
a The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed
by coronary angiography in patients with coronary disease and moderate hypercholesterolemia
(baseline LDL-C range: 130-190 mg/dL). In this double-blind, multicenter, controlled clinical
trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the
difference between pravastatin and placebo for the primary endpoint (per-patient change in mean
26
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coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter
stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum
lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment
group (p=0.02).
In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by
coronary angiography in 885 patients with angina pectoris, angiographically documented
coronary artery disease, and hypercholesterolemia (baseline total cholesterol range:
160-310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were
evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of
coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by
changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, PLAC II,8 REGRESS, and KAPS9 studies (combined
N=1891) showed that treatment with pravastatin was associated with a statistically significant
reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo
versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to
reduce the rate of nonfatal MI.
14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)
PRAVACHOL is highly effective in reducing Total-C, LDL-C, and TG in patients with
heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary
hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week,
and the maximum response usually is achieved within 4 weeks. This response is maintained
during extended periods of therapy. In addition, PRAVACHOL is effective in reducing the risk
of acute coronary events in hypercholesterolemic patients with and without previous MI.
A single daily dose is as effective as the same total daily dose given twice a day. In multicenter,
double-blind, placebo-controlled studies of patients with primary hypercholesterolemia,
treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly
decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7).
In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with
primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277)
significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from
27
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baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the
individual studies were consistent with the pooled data (see Table 7).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across all
doses produced variable increases in HDL-C (see Table 7).
Table 7:
Primary Hypercholesterolemia Studies: Dose Response of
PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeksa
Placebo (N=36)
−3%
−4%
+1%
−4%
10 mg (N=18)
−16%
−22%
+7%
−15%
20 mg (N=19)
−24%
−32%
+2%
−11%
40 mg (N=18)
−25%
−34%
+12%
−24%
Mean Percent Changes From Baseline After 6 Weeksb
Placebo (N=162)
0%
−1%
−1%
+1%
80 mg (N=277)
−27%
−37%
+3%
−19%
a A multicenter, double-blind, placebo-controlled study.
b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.
In another clinical trial, patients treated with pravastatin in combination with cholestyramine
(70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or
greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced
increases in TG levels (which are themselves of uncertain clinical significance).
14.4
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200 mg/dL
and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For
pravastatin-treated subjects, the median (min, max) baseline TG level was 246.0 (200.5,
349.5) mg/dL (see Table 8.)
Table 8:
Patients with Fredrickson Type IV Hyperlipidemia Median (25th, 75th
percentile) % Change from Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
TG
−21.1 (−34.8, 1.3)
−6.3 (−23.1, 18.3)
Total-C
−22.1 (−27.1, −14.8)
0.2 (−6.9, 6.8)
LDL-C
−31.7 (−39.6, −21.5)
0.7 (−9.0, 10.0)
28
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Table 8:
Patients with Fredrickson Type IV Hyperlipidemia Median (25th, 75th
percentile) % Change from Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
HDL-C
7.4 (−1.2, 17.7)
2.8 (−5.7, 11.7)
Non-HDL-C
−27.2 (−34.0, −18.5)
−0.8 (−8.2, 7.0)
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with genotype
E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 9.
Table 9:
Patients with Fredrickson Type III Dysbetalipoproteinemia Median
(min, max) % Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
−32.7 (−58.5, 4.6)
TG
443.0 (275.0, 1299.0)
−23.7 (−68.5, 44.7)
VLDL-Ca
206.5 (110.0, 379.0)
−43.8 (−73.1, −14.3)
LDL-Ca
117.5 (80.0, 170.0)
−40.8 (−63.7, 4.6)
HDL-C
30.0 (18.0, 88.0)
6.4 (−45.0, 105.6)
Non-HDL-C
344.5 (215.0, 646.0)
−36.7 (−66.3, 5.8)
a N=14
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
−31.4 (−54.5, −13.0)
TG
343.2 (212.6, 845.9)
−11.9 (−56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
−35.7 (−74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
−30.3 (−52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (−17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
−35.5 (−81.0, −13.5)
29
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14.6
Pediatric Clinical Study
A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2
years. The children (aged 8-13 years) were randomized to placebo (N=63) or 20 mg of
pravastatin daily (N=65) and the adolescents (aged 14-18 years) were randomized to placebo
(N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level
>95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of
familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL
in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL) groups,
respectively.
Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children
and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was
similar.
Table 10:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients with
Heterozygous Familial Hypercholesterolemia: Least-Squares Mean %
Change from Baseline at Month 24 (Last Observation Carried
Forward: Intent-to-Treat)a
Pravastatin
20 mg
(Aged 8-13
years)
N=65
Pravastatin
40 mg
(Aged 14-18
years)
N=41
Combined
Pravastatin
(Aged 8-18
years)
N=106
Combined
Placebo
(Aged 8-18
years)
N=108
95% CI of the
Difference Between
Combined
Pravastatin and
Placebo
LDL-C
−26.04b
−21.07b
−24.07b
−1.52
(−26.74, −18.86)
TC
−20.75b
−13.08b
−17.72b
−0.65
(−20.40, −13.83)
HDL-C
1.04
13.71
5.97
3.13
(−1.71, 7.43)
TG
−9.58
−0.30
−5.88
−3.27
(−13.95, 10.01)
ApoB
(N)
−23.16b
(61)
−18.08b
(39)
−21.11b
(100)
−0.97
(106)
(−24.29, −16.18)
a The above least-squares mean values were calculated based on log-transformed lipid values.
b Significant at p≤0.0001 when compared with placebo.
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin group
compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
30
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The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children.
The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
15
REFERENCES
1. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to
mechanisms and disorders. N Engl J Med. 1967;276: 34-44, 94-103, 148-156, 215-225,
273-281.
2. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of
lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol. 1996;10(6):439-446.
3. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study
Group (WOS). Prevention of coronary heart disease with pravastatin in men with
hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
4. The Long-term Intervention with Pravastatin in Ischemic Disease Group (LIPID). Prevention
of cardiovascular events and death with pravastatin in patients with coronary heart disease
and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
5. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial
Investigators (CARE). The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
6. Pitt B, Mancini GBJ, Ellis SG, et al, for the PLAC I Investigators. Pravastatin limitation of
atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression
and clinical events. J Am Coll Cardiol. 1995;26:1133-1139.
7. Jukema JW, Bruschke AVG, van Boven AJ, et al, for the Regression Growth Evaluation
Statin Study Group (REGRESS). Effects of lipid lowering by pravastatin on progression and
regression of coronary artery disease in symptomatic man with normal to moderately
elevated serum cholesterol levels. Circ. 1995;91:2528-2540.
8. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the
carotid arteries: Design features of a clinical trial with carotid atherosclerosis outcome
(PLAC II). Control Clin Trials. 1992;13:495-506.
9. Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study
31
Reference ID: 2948362
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For current labeling information, please visit https://www.fda.gov/drugsatfda
(KAPS). A population-based primary preventive trial of the effect of LDL lowering on
atherosclerotic progression in carotid and femoral arteries. Circ. 1995;92:1758-1764.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
PRAVACHOL (pravastatin sodium) Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 10” engraved on the opposite side. They are supplied in bottles of
90 (NDC 0003-5154-05). Bottles contain a desiccant canister.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5178-05). Bottles contain a desiccant canister.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5194-10). Bottles contain a desiccant canister.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
They are supplied in bottles of 90 (NDC 0003-5195-10). Bottles contain a desiccant canister.
16.2
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.
17
PATIENT COUNSELING INFORMATION
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1)].
32
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Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
1186935A3
Rev May 2011
Reference ID: 2948362
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---------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------
----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
ERIC C COLMAN
05/18/2011
Reference ID: 2948362
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|
custom-source
|
2025-02-12T13:46:15.759648
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019898s061lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 61}
|
11,828
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRAVACHOL safely and effectively. See full prescribing information for
PRAVACHOL.
PRAVACHOL (pravastatin sodium) Tablets
Initial U.S. Approval: 1991
-----------------------------INDICATIONS AND USAGE-----------------------------
PRAVACHOL is an HMG-CoA reductase inhibitor (statin) indicated as an
adjunctive therapy to diet to:
Reduce the risk of MI, revascularization, and cardiovascular mortality in
hypercholesterolemic patients without clinically evident CHD. (1.1)
Reduce the risk of total mortality by reducing coronary death, MI,
revascularization,
stroke/TIA,
and
the
progression
of
coronary
atherosclerosis in patients with clinically evident CHD. (1.1)
Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase
HDL-C in patients with primary hypercholesterolemia and mixed
dyslipidemia. (1.2)
Reduce elevated serum TG levels in patients with hypertriglyceridemia.
(1.2)
Treat patients with primary dysbetalipoproteinemia who are not responding
to diet. (1.2)
Treat children and adolescent patients ages 8 years and older with
heterozygous familial hypercholesterolemia after failing an adequate trial
of diet therapy. (1.2)
Limitations of use:
PRAVACHOL has not been studied in Fredrickson Types I and V
dyslipidemias. (1.3)
-----------------------------DOSAGE AND ADMINISTRATION-------------------
Adults: the recommended starting dose is 40 mg once daily. Use 80 mg
dose only for patients not reaching LDL-C goal with 40 mg. (2.2)
Significant renal impairment: the recommended starting dose is 10 mg once
daily. (2.2)
Children (ages 8 to 13 years, inclusive): the recommended starting dose is
20 mg once daily. (2.3)
Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg
once daily. (2.3)
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Prevention of Cardiovascular Disease
1.2
Hyperlipidemia
1.3
Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
2.2
Adult Patients
2.3
Pediatric Patients
2.4
Concomitant Lipid-Altering Therapy
2.5
Dosage in Patients Taking Cyclosporine
2.6
Dosage in Patients Taking Clarithromycin
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Hypersensitivity
4.2
Liver
4.3
Pregnancy
4.4
Nursing Mothers
5
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle
5.2
Liver
5.3
Endocrine Function
6
ADVERSE REACTIONS
6.1
Adverse Clinical Events
6.2
Postmarketing Experience
6.3
Laboratory Test Abnormalities
6.4
Pediatric Patients
7
DRUG INTERACTIONS
7.1
Cyclosporine
7.2
Clarithromycin
7.3
Colchicine
7.4
Gemfibrozil
7.5
Other Fibrates
---------------------------DOSAGE FORMS AND STRENGTHS-------------------
Tablets: 10 mg, 20 mg, 40 mg, 80 mg. (3)
--------------------------------CONTRAINDICATIONS-------------------------------
Hypersensitivity to any component of this medication. (4.1, 6.2, 11)
Active liver disease or unexplained, persistent elevations of serum
transaminases. (4.2, 5.2)
Women who are pregnant or may become pregnant. (4.3, 8.1)
Nursing mothers. (4.4, 8.3)
----------------------------WARNINGS AND PRECAUTIONS----------------------
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing
factors include advanced age (>65), uncontrolled hypothyroidism, and
renal impairment. Patients should be advised to report promptly any
symptoms of myopathy. Pravastatin therapy should be discontinued if
myopathy is diagnosed or suspected. (5.1, 8.5)
Liver enzyme abnormalities: persistent elevations in hepatic transaminases
can occur. Check liver enzyme tests before initiating therapy and as
clinically indicated thereafter. (5.2)
-----------------------------------ADVERSE REACTIONS-----------------------------
In short-term clinical trials, the most commonly reported adverse reactions (≥2%
and > placebo) regardless of causality were: musculoskeletal pain,
nausea/vomiting, upper respiratory infection, diarrhea, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------------DRUG INTERACTIONS----------------------------
Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying
doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle
effects. Caution should be used when prescribing with PRAVACHOL. (7)
Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg
once daily. (2.5, 7.1)
Clarithromycin: combination increases exposure. Limit pravastatin to
40 mg once daily. (2.6, 7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: TBD
7.6
Niacin
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Homozygous Familial Hypercholesterolemia
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Prevention of Coronary Heart Disease
14.2
Secondary Prevention of Cardiovascular Events
14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and
IIb)
14.4
Hypertriglyceridemia (Fredrickson Type IV)
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
14.6
Pediatric Clinical Study
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
1
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor
intervention in individuals at significantly increased risk for atherosclerotic vascular disease due
to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a
diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has
been inadequate.
1.1
Prevention of Cardiovascular Disease
In hypercholesterolemic patients without clinically evident coronary heart disease (CHD),
PRAVACHOL (pravastatin sodium) is indicated to:
reduce the risk of myocardial infarction (MI).
reduce the risk of undergoing myocardial revascularization procedures.
reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular
causes.
In patients with clinically evident CHD, PRAVACHOL is indicated to:
reduce the risk of total mortality by reducing coronary death.
reduce the risk of MI.
reduce the risk of undergoing myocardial revascularization procedures.
reduce the risk of stroke and stroke/transient ischemic attack (TIA).
slow the progression of coronary atherosclerosis.
1.2
Hyperlipidemia
PRAVACHOL is indicated:
as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase
high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia
and mixed dyslipidemia (Fredrickson Types IIa and IIb).1
as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson
Type IV).
for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III)
who do not respond adequately to diet.
2
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as an adjunct to diet and lifestyle modification for treatment of heterozygous familial
hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if
after an adequate trial of diet the following findings are present:
a. LDL-C remains ≥190 mg/dL or
b. LDL-C remains ≥160 mg/dL and:
there is a positive family history of premature cardiovascular disease (CVD) or
two or more other CVD risk factors are present in the patient.
1.3
Limitations of Use
PRAVACHOL has not been studied in conditions where the major lipoprotein abnormality is
elevation of chylomicrons (Fredrickson Types I and V).
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL and should continue on this diet during treatment with PRAVACHOL [see
NCEP Treatment Guidelines for details on dietary therapy].
2.2
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve
desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal
impairment, a starting dose of 10 mg daily is recommended. PRAVACHOL can be administered
orally as a single dose at any time of the day, with or without food. Since the maximal effect of a
given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time
and dosage adjusted according to the patient’s response to therapy and established treatment
guidelines.
2.3
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than
20 mg have not been studied in this patient population.
3
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Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses
greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be reevaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C [see Indications and Usage (1.2)].
2.4
Concomitant Lipid-Altering Therapy
PRAVACHOL may be used with bile acid resins. When administering a bile-acid-binding resin
(e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given either 1 hour
or more before or at least 4 hours following the resin. [See Clinical Pharmacology (12.3).]
2.5
Dosage in Patients Taking Cyclosporine
In patients taking immunosuppressive drugs such as cyclosporine concomitantly with
pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and
titration to higher doses should be done with caution. Most patients treated with this combination
received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine,
therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and
Precautions (5.1) and Drug Interactions (7.1)].
2.6
Dosage in Patients Taking Clarithromycin
In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once
daily [see Drug Interactions (7.2)].
3
DOSAGE FORMS AND STRENGTHS
PRAVACHOL Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 10” engraved on the opposite side.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side.
4
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40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
4
CONTRAINDICATIONS
4.1
Hypersensitivity
Hypersensitivity to any component of this medication.
4.2
Liver
Active liver disease or unexplained, persistent elevations of serum transaminases [see Warnings
and Precautions (5.2)].
4.3
Pregnancy
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
components for fetal development (including synthesis of steroids and cell membranes). Since
statins decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in nursing
mothers.
PRAVASTATIN
SHOULD
BE
ADMINISTERED
TO
WOMEN
OF
CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO
CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient
becomes pregnant while taking this class of drug, therapy should be discontinued immediately
and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations
(8.1)].
4.4
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because statins have the
potential for serious adverse reactions in nursing infants, women who require PRAVACHOL
treatment should not breast-feed their infants [see Use in Specific Populations (8.3)].
5
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5
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have
been reported with pravastatin and other drugs in this class. A history of renal impairment
may be a risk factor for the development of rhabdomyolysis. Such patients merit closer
monitoring for skeletal muscle effects.
Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse
Reactions (6)]. Myopathy, defined as muscle aching or muscle weakness in conjunction with
increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of
normal (ULN), was rare (<0.1%) in pravastatin clinical trials. Myopathy should be considered in
any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of
CPK. Predisposing factors include advanced age (>65), uncontrolled hypothyroidism, and renal
impairment. Patients should be advised to report promptly unexplained muscle pain, tenderness,
or weakness, particularly if accompanied by malaise or fever. Pravastatin therapy should be
discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Pravastatin therapy should also be temporarily withheld in any patient experiencing an
acute or serious condition predisposing to the development of renal failure secondary to
rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic,
endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy during treatment with statins is increased with concurrent therapy with
either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant
increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant
patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to
40 mg and cyclosporine. Some of these patients also received other concomitant
immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who
were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil
(1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations
versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK
elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving
combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin
monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The
6
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benefit of further alterations in lipid levels by the combined use of PRAVACHOL with
fibrates should be carefully weighed against the potential risks of this combination.
Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin
coadministered with colchicine, and caution should be exercised when prescribing pravastatin
with colchicine [see Drug Interactions (7.3)].
5.2
Liver
Statins, like some other lipid-lowering therapies, have been associated with biochemical
abnormalities of liver function. In 3 long-term (4.8-5.9 years), placebo-controlled clinical trials
(WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or
placebo [see Clinical Studies (14)]. In an analysis of serum transaminase values (ALT, AST),
incidences of marked abnormalities were compared between the pravastatin and placebo
treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3
times the upper limit of normal for subjects with pretreatment values less than or equal to the
upper limit of normal, or 4 times the pretreatment value for subjects with pretreatment values
greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked
abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment
groups. Overall, clinical trial experience showed that liver function test abnormalities observed
during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did
not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial,
subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or non
alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months.
The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the
upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a
doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at
baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the
prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo.
Conclusions regarding liver safety are limited since the study was not large enough to establish
similarity between groups (with 95% confidence) in the rates of ALT elevation.
It is recommended that liver function tests be performed prior to the initiation of therapy
and when clinically indicated.
Active liver disease or unexplained persistent transaminase elevations are contraindications to
the use of pravastatin [see Contraindications (4.2)]. Caution should be exercised when
7
Reference ID: 3090896
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pravastatin is administered to patients who have a recent (<6 months) history of liver disease,
have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations,
jaundice), or are heavy users of alcohol.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients
taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment with PRAVACHOL, promptly interrupt
therapy. If an alternate etiology is not found do not restart PRAVACHOL.
5.3
Endocrine Function
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such,
might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials
with pravastatin in males and post-menopausal females were inconsistent with regard to possible
effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone
response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of
treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change significantly
after therapy in these patients. The effects of statins on spermatogenesis and fertility have not
been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-
gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who
display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution
should also be exercised if a statin or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may
diminish the levels or activity of steroid hormones.
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated
with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18
years) for 2 years, there were no detectable differences seen in any of the endocrine parameters
(ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to
placebo. There were no detectable differences seen in height and weight changes, testicular
volume changes, or Tanner score relative to placebo.
6
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In
4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of
8
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placebo-treated patients were discontinued from treatment because of adverse experiences
attributed to study drug therapy; this difference was not statistically significant.
6.1
Adverse Clinical Events
Short-Term Controlled Trials
In the PRAVACHOL placebo-controlled clinical trials database of 1313 patients (age range
20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2%
Others) with a median treatment duration of 14 weeks, 3.3% of patients on PRAVACHOL and
1.2% patients on placebo discontinued due to adverse events regardless of causality. The most
common adverse reactions that led to treatment discontinuation and occurred at an incidence
greater than placebo were: liver function test increased, nausea, anxiety/depression, and
dizziness.
All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated
patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:
Table 1:
Adverse Events in 2% of Patients Treated with Pravastatin 5 to
40 mg and at an Incidence Greater Than Placebo in Short-Term
Placebo-Controlled Trials (% of patients)
Body System/Event
5 mg
N=100
10 mg
N=153
20 mg
N=478
40 mg
N=171
Any Dose
N=902
Placebo
N=411
Cardiovascular
Angina Pectoris
5.0
4.6
4.8
3.5
4.5
3.4
Dermatologic
Rash
3.0
2.6
6.7
1.2
4.5
1.4
Gastrointestinal
Nausea/Vomiting
Diarrhea
Flatulence
Dyspepsia/Heartburn
Abdominal Distension
4.0
8.0
2.0
0.0
2.0
5.9
8.5
3.3
3.3
3.3
10.5
6.5
4.6
3.6
2.1
2.3
4.7
0.0
0.6
0.6
7.4
6.7
3.2
2.5
2.0
7.1
5.6
4.4
2.7
2.4
General
Fatigue
Chest Pain
Influenza
4.0
4.0
4.0
1.3
1.3
2.6
5.2
3.3
1.9
0.0
1.2
0.6
3.4
2.7
2.0
3.9
1.9
0.7
Musculoskeletal
Musculoskeletal Pain
13.0
3.9
13.2
5.3
10.1
10.2
Myalgia
1.0
2.6
2.9
1.2
2.3
1.2
9
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Table 1:
Adverse Events in 2% of Patients Treated with Pravastatin 5 to
40 mg and at an Incidence Greater Than Placebo in Short-Term
Placebo-Controlled Trials (% of patients)
Body System/Event
5 mg
N=100
10 mg
N=153
20 mg
N=478
40 mg
N=171
Any Dose
N=902
Placebo
N=411
Nervous System
Headache
Dizziness
5.0
4.0
6.5
1.3
7.5
5.2
3.5
0.6
6.3
3.5
4.6
3.4
Respiratory
Pharyngitis
Upper Respiratory Infection
Rhinitis
Cough
2.0
6.0
7.0
4.0
4.6
9.8
5.2
1.3
1.5
5.2
3.8
3.1
1.2
4.1
1.2
1.2
2.0
5.9
3.9
2.5
2.7
5.8
4.9
1.7
Investigation
ALT Increased
g-GT Increased
CPK Increased
2.0
3.0
5.0
2.0
2.6
1.3
4.0
2.1
5.2
1.2
0.6
2.9
2.9
2.0
4.1
1.2
1.2
3.6
The safety and tolerability of PRAVACHOL at a dose of 80 mg in 2 controlled trials with a
mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses except that 4
out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN
compared to 0 out of 115 patients taking 40 mg of pravastatin.
Long-Term Controlled Morbidity and Mortality Trials
In the PRAVACHOL placebo-controlled clinical trials database of 21,483 patients (age range
24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians,
0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of
patients on PRAVACHOL and 9.3% patients on placebo discontinued due to adverse events
regardless of causality.
Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland
Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term
Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of
Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis
in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and
Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated
with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability
profile in the pravastatin group was comparable to that of the placebo group. Patients were
10
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exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9
years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common
reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively,
these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse
events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these
studies are identified in Table 2.
Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Dermatologic
Rash (including dermatitis)
7.2
7.1
General
Edema
3.0
2.7
Fatigue
8.4
7.8
Chest Pain
10.0
9.8
Fever
2.1
1.9
Weight Gain
3.8
3.3
Weight Loss
3.3
2.8
Musculoskeletal
Musculoskeletal Pain
24.9
24.4
Muscle Cramp
5.1
4.6
Musculoskeletal Traumatism
10.2
9.6
Nervous System
Dizziness
7.3
6.6
Sleep Disturbance
3.0
2.4
Anxiety/Nervousness
4.8
4.7
Paresthesia
3.2
3.0
Renal/Genitourinary
Urinary Tract Infection
2.7
2.6
Respiratory
Upper Respiratory Tract Infection
21.2
20.2
Cough
8.2
7.4
Influenza
9.2
9.0
Pulmonary Infection
3.8
3.5
Sinus Abnormality
7.0
6.7
Tracheobronchitis
3.4
3.1
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
3.4
3.3
Infections
11
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Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Viral Infection
3.2
2.9
In addition to the events listed above in the long-term trials table, events of probable, possible, or
uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the
long-term trials included the following:
Dermatologic: scalp hair abnormality (including alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
General: flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral
neuropathy).
Special Senses: taste disturbance.
6.2
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following events
have been reported rarely during postmarketing experience with PRAVACHOL, regardless of
causality assessment:
Musculoskeletal: myopathy, rhabdomyolysis.
Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment
of extraocular movement, facial paresis), peripheral nerve palsy.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These
12
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cognitive issues have been reported for all statins. The reports are generally nonserious, and
reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and
symptom resolution (median of 3 weeks).
Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR
increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal
necrolysis, erythema multiforme (including Stevens-Johnson syndrome).
Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active
hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis,
hepatoma, fatal and non-fatal hepatic failure.
Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Renal: urinary abnormality (including dysuria, frequency, nocturia).
Respiratory: dyspnea.
Reproductive: gynecomastia.
Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.
6.3
Laboratory Test Abnormalities
Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions
(5.1, 5.2)].
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to
normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been
reported with statins.
6.4
Pediatric Patients
In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH
(n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1%
Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.
13
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[See Warnings and Precautions (5.3), Use in Specific Populations (8.4), and Clinical
Pharmacology (12.3).]
7
DRUG INTERACTIONS
For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or
erythromycin, the risk of myopathy increases [see Warnings and Precautions (5.1) and
Clinical Pharmacology (12.3)].
7.1
Cyclosporine
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see
Dosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology
(12.3)].
7.2
Clarithromycin
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin
[see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical
Pharmacology (12.3)].
7.3
Colchicine
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine
[see Warnings and Precautions (5.1)].
7.4
Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are
coadministered with gemfibrozil, concomitant administration of PRAVACHOL with gemfibrozil
should be avoided [see Warnings and Precautions (5.1)].
14
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7.5
Other Fibrates
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase
inhibitors is increased with concurrent administration of other fibrates, PRAVACHOL should be
administered with caution when used concomitantly with other fibrates [see Warnings and
Precautions (5.1)].
7.6
Niacin
The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination
with niacin; a reduction in PRAVACHOL dosage should be considered in this setting [see
Warnings and Precautions (5.1)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category X
[See Contraindications (4.3).]
Safety in pregnant women has not been established. Available data in women inadvertently
taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are
no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether
pravastatin can cause fetal harm when administered to a pregnant woman or can affect
reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit
outweighs the potential risk to the fetus and patients have been informed of the potential hazards.
Rare reports of congenital anomalies have been received following intrauterine exposure to other
statins. In a review2 of approximately 100 prospectively followed pregnancies in women
exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous
abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate to exclude a ≥3- to 4-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed pregnancies,
drug treatment was initiated prior to pregnancy and was discontinued at some point in the first
trimester when pregnancy was identified. As safety in pregnant women has not been established
and there is no apparent benefit to therapy with PRAVACHOL during pregnancy [see
15
Reference ID: 3090896
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Contraindications (4.3)], treatment should be immediately discontinued as soon as pregnancy is
recognized. PRAVACHOL should be administered to women of childbearing potential only
when such patients are highly unlikely to conceive and have been informed of the potential
hazards.
Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in
rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times
(rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on
surface area (mg/m2).
In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation
days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were
observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day
MRHD based on body surface area (mg/m2).
In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17
through lactation day 21 (weaning) increased mortality of offspring and developmental delays
were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day
MRHD based on body surface area (mg/m2).
8.3
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential for
serious adverse reactions in nursing infants, women taking PRAVACHOL should not nurse [see
Contraindications (4.4)].
Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels
following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in
lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels
than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.
8.4
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8 to 18 years of
age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with
pravastatin had an adverse experience profile generally similar to that of patients treated with
placebo with influenza and headache commonly reported in both treatment groups. [See Adverse
16
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Reactions (6.4).] Doses greater than 40 mg have not been studied in this population.
Children and adolescent females of childbearing potential should be counseled on appropriate
contraceptive methods while on pravastatin therapy [see Contraindications (4.3) and Use in
Specific Populations (8.1)]. For dosing information [see Dosage and Administration (2.3).]
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not
been conducted.
8.5
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593
subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies,
36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The
beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in
modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in
the elderly was similar to that in the overall population. Other reported clinical experience has
not identified differences in responses to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25%-50%) higher in elderly subjects than in healthy young
subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma
concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial
accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology
(12.3)].
Since advanced age (≥65 years) is a predisposing factor for myopathy, PRAVACHOL should be
prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
8.6
Homozygous Familial Hypercholesterolemia
Pravastatin
has
not
been
evaluated
in
patients
with
rare
homozygous
familial
hypercholesterolemia. In this group of patients, it has been reported that statins are less effective
because the patients lack functional LDL receptors.
17
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10
OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs,
it should be treated symptomatically with laboratory monitoring and supportive measures should
be instituted as required.
11
DESCRIPTION
PRAVACHOL (pravastatin sodium) is one of a class of lipid-lowering compounds, the statins,
which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a
hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium
salt,
[1S
[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.
Structural formula: chemical structure
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively
polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It
is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically
insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg tablets.
Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide, magnesium
18
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stearate, microcrystalline cellulose, and povidone. The 10 mg tablet also contains Red Ferric
Oxide, the 20 mg and 80 mg tablets also contain Yellow Ferric Oxide, and the 40 mg tablet also
contains Green Lake Blend (mixture of D&C Yellow No. 10-Aluminum Lake and FD&C Blue
No. 1-Aluminum Lake).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces
VLDL and TG and increases HDL-C.
12.3
Pharmacokinetics
General
Absorption: PRAVACHOL is administered orally in the active form. In studies in man, peak
plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on
urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and
absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or
1 hour prior to meals.
Pravastatin plasma concentrations, including area under the concentration-time curve (AUC),
Cmax, and steady-state minimum (Cmin), are directly proportional to administered dose. Systemic
bioavailability of pravastatin administered following a bedtime dose was decreased 60%
compared to that following an AM dose. Despite this decrease in systemic bioavailability, the
efficacy of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose.
The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. The geometric means of pravastatin Cmax and AUC following a 20 mg dose in the fasted
state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.
19
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Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin
accumulation following once or twice daily administration of PRAVACHOL tablets.
Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.
Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to
6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring
hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40
the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes
extensive first-pass extraction in the liver (extraction ratio 0.66).
Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the
feces. After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes
(i.e., biliary excretion and biotransformation).
Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for
pravastatin is 1.8 hours in humans.
Specific Populations
Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients
with varying degrees of renal impairment (as determined by creatinine clearance). No effect was
observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite
(SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal
impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour
shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).
Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy
confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for
cirrhotic patients compared to 6-fold for healthy subjects. [See Warnings and Precautions (5.2).]
Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin
was approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65-75 years old) compared with younger men (19-31
years old). In a similar study conducted in women, the mean AUC for pravastatin was
approximately 46% higher and the mean CUE approximately 18% lower in elderly women
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(65-78 years old) compared with younger women (18-38 years old). In both studies, Cmax, Tmax,
and t½ values were similar in older and younger subjects. [See Use in Specific Populations (8.5).]
Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric
means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for Cmax
were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No
conclusion can be made based on these findings due to the small number of samples and large
variability. [See Use in Specific Populations (8.4).]
Drug-Drug Interactions
Table 3:
Effect of Coadministered Drugs on the Pharmacokinetics of
Pravastatin
Coadministered Drug and Dosing
Regimen
Pravastatin
Dose (mg)
Change in AUC
Change in Cmax
Cyclosporine 5 mg/kg single dose
40 mg single dose
282%
327%
Clarithromycin 500 mg BID for 9 days
40 mg OD for 8 days
110%
128%
Darunavir 600 mg BID/Ritonavir 100 mg
BID for 7 days
40 mg single dose
81%
63%
Colestipol 10 g single dose
20 mg single dose
47%
53%
Cholestyramine 4 g single dose
Administered simultaneously
Administered 1 hour prior to
cholestyramine
Administered 4 hours after
cholestyramine
20 mg single dose
40%
12%
12%
39%
30%
6.8%
Cholestyramine 24 g OD for 4 weeks
20 mg BID for 8 weeks
5 mg BID for 8 weeks
10 mg BID for 8 weeks
51%
38%
18%
4.9%
23%
33%
Fluconazole
200 mg IV for 6 days
200 mg PO for 6 days
20 mg PO+10 mg IV
20 mg PO+10 mg IV
34%
16%
33%
16%
Kaletra 400 mg/100 mg BID for 14 days
20 mg OD for 4 days
33%
26%
Verapamil IR 120 mg for 1 day and
Verapamil ER 480 mg for 3 days
40 mg single dose
31%
42%
Cimetidine 300 mg QID for 3 days
20 mg single dose
30%
9.8%
Antacids 15 mL QID for 3 days
20 mg single dose
28%
24%
21
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Table 3:
Effect of Coadministered Drugs on the Pharmacokinetics of
Pravastatin
Coadministered Drug and Dosing
Regimen
Pravastatin
Dose (mg)
Change in AUC
Change in Cmax
Digoxin 0.2 mg OD for 9 days
20 mg OD for 9 days
23%
26%
Probucol 500 mg single dose
20 mg single dose
14%
24%
Warfarin 5 mg OD for 6 days
20 mg BID for 6 days
13%
6.7%
Itraconazole 200 mg OD for 30 days
40 mg OD for 30 days
11% (compared to
Day 1)
17% (compared
to Day 1)
Gemfibrozil 600 mg single dose
20 mg single dose
7.0%
20%
Aspirin 324 mg single dose
20 mg single dose
4.7%
8.9%
Niacin 1 g single dose
20 mg single dose
3.6%
8.2%
Diltiazem
20 mg single dose
2.7%
30%
Grapefruit juice
40 mg single dose
1.8%
3.7%
BID = twice daily; OD = once daily; QID = four times daily
Table 4:
Effect of Pravastatin on the Pharmacokinetics of Coadministered
Drugs
Pravastatin Dosing
Regimen
Name and Dose
Change in AUC
Change in Cmax
20 mg BID for 6 days
Warfarin 5 mg OD for 6 days
Change in mean prothrombin time
17%
0.4 sec
15%
20 mg OD for 9 days
Digoxin 0.2 mg OD for 9 days
4.6%
5.3%
20 mg BID for 4 weeks
10 mg BID for 4 weeks
5 mg BID for 4 weeks
Antipyrine 1.2 g single dose
3.0%
1.6%
Less than 1%
Not Reported
20 mg OD for 4 days
Kaletra 400 mg/100 mg BID for
14 days
No change
No change
BID = twice daily; OD = once daily
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was
an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These
22
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effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on
body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013).
These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times
(500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up
to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on
AUC), there were no drug-induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella
typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma
cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using
Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a
dominant lethal test in mice or a micronucleus test in mice.
In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance.
13.2
Animal Toxicology and/or Pharmacology
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear
cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of
25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of
80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other
drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion
starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher
than the mean drug level in humans taking the highest recommended dose (as measured by total
enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at
23
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180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the
60 mg/kg/day dose.
When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5-45 mg/kg/day), no
drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-
weight gain was observed during the dosing and 52-day recovery periods as well as slight
thinning of the corpus callosum at the end of the recovery period. This finding was not evident in
rats examined at the completion of the dosing period and was not associated with any
inflammatory or degenerative changes in the brain. The biological relevance of the corpus
callosum finding is uncertain due to the absence of any other microscopic changes in the brain or
peripheral nervous tissue and because it occurred at the end of the recovery period.
Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-
maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day
during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are
approximately 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus
callosum was observed in rats dosed with pravastatin (250 mg/kg/day) beginning PND 35 for 3
months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately
equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the
40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.
14
CLINICAL STUDIES
14.1
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (WOS),3 the effect of PRAVACHOL on fatal and
nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with
LDL-C levels between 156 to 254 mg/dL (4-6.7 mmol/L). In this randomized, double-blind,
placebo-controlled study, patients were treated with standard care, including dietary advice, and
either PRAVACHOL 40 mg daily (N=3302) or placebo (N=3293) and followed for a median
duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6
months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7),
−27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either CHD death or
nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus
174 events in the PRAVACHOL group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure
24
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below]). The risk reduction with PRAVACHOL was similar and significant throughout the entire
range of baseline LDL cholesterol levels. This reduction was also similar and significant across
the age range studied with a 40% risk reduction for patients younger than 55 years and a 27%
risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included
only men, and therefore it is not clear to what extent these data can be extrapolated to a similar
population of female patients. Coronary Heart Disease Death or Nonfatal Myocardial Infarction Survival Distributors
PRAVACHOL also significantly decreased the risk for undergoing myocardial revascularization
procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary
angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31%
(128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and
there was no increase in death from non-cardiovascular causes.
14.2
Secondary Prevention of Cardiovascular Events
In the LIPID4 study, the effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients
(7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris
(3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind,
placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at
randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46
and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and
HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving
aspirin and 76% were receiving antihypertensive medication. Treatment with PRAVACHOL
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significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The
risk reduction due to treatment with PRAVACHOL on CHD mortality was consistent regardless
of age. PRAVACHOL significantly reduced the risk for total mortality (by reducing CHD death)
and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of
either MI or hospitalization for unstable angina pectoris.
Table 5:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=4512)
Placebo
(N=4502)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or nonfatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the CARE5 study, the effect of PRAVACHOL, 40 mg daily, on CHD death and nonfatal MI
was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the
preceding 3 to 20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled
study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL.
LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At
baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive
medications. Median (25th, 75th percentile) percent changes from baseline after 6 months
of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4
(−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with
PRAVACHOL significantly reduced the rate of first recurrent coronary events (either CHD
death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and
the risk for stroke or TIA (see Table 6).
26
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Table 6:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=2081)
Placebo
(N=2078)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality or nonfatal MIa
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
<0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
a The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed
by coronary angiography in patients with coronary disease and moderate hypercholesterolemia
(baseline LDL-C range: 130-190 mg/dL). In this double-blind, multicenter, controlled clinical
trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the
difference between pravastatin and placebo for the primary endpoint (per-patient change in mean
coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter
stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum
lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment
group (p=0.02).
In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by
coronary angiography in 885 patients with angina pectoris, angiographically documented
coronary artery disease, and hypercholesterolemia (baseline total cholesterol range:
160-310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were
evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of
coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by
changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, PLAC II,8 REGRESS, and KAPS9 studies (combined
N=1891) showed that treatment with pravastatin was associated with a statistically significant
reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo
versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to
reduce the rate of nonfatal MI.
27
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14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)
PRAVACHOL is highly effective in reducing Total-C, LDL-C, and TG in patients with
heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary
hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week,
and the maximum response usually is achieved within 4 weeks. This response is maintained
during extended periods of therapy. In addition, PRAVACHOL is effective in reducing the risk
of acute coronary events in hypercholesterolemic patients with and without previous MI.
A single daily dose is as effective as the same total daily dose given twice a day. In multicenter,
double-blind, placebo-controlled studies of patients with primary hypercholesterolemia,
treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly
decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7).
In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with
primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277)
significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from
baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the
individual studies were consistent with the pooled data (see Table 7).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across all
doses produced variable increases in HDL-C (see Table 7).
Table 7:
Primary Hypercholesterolemia Studies: Dose Response of
PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeksa
Placebo (N=36)
−3%
−4%
+1%
−4%
10 mg (N=18)
−16%
−22%
+7%
−15%
20 mg (N=19)
−24%
−32%
+2%
−11%
40 mg (N=18)
−25%
−34%
+12%
−24%
Mean Percent Changes From Baseline After 6 Weeksb
Placebo (N=162)
0%
−1%
−1%
+1%
80 mg (N=277)
−27%
−37%
+3%
−19%
a A multicenter, double-blind, placebo-controlled study.
b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.
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In another clinical trial, patients treated with pravastatin in combination with cholestyramine
(70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or
greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced
increases in TG levels (which are themselves of uncertain clinical significance).
14.4
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200 mg/dL
and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For
pravastatin-treated subjects, the median (min, max) baseline TG level was 246.0 (200.5,
349.5) mg/dL (see Table 8.)
Table 8:
Patients with Fredrickson Type IV Hyperlipidemia Median (25th, 75th
percentile) % Change from Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
TG
−21.1 (−34.8, 1.3)
−6.3 (−23.1, 18.3)
Total-C
−22.1 (−27.1, −14.8)
0.2 (−6.9, 6.8)
LDL-C
−31.7 (−39.6, −21.5)
0.7 (−9.0, 10.0)
HDL-C
7.4 (−1.2, 17.7)
2.8 (−5.7, 11.7)
Non-HDL-C
−27.2 (−34.0, −18.5)
−0.8 (−8.2, 7.0)
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with genotype
E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 9.
Table 9:
Patients with Fredrickson Type III Dysbetalipoproteinemia Median
(min, max) % Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
−32.7 (−58.5, 4.6)
TG
443.0 (275.0, 1299.0)
−23.7 (−68.5, 44.7)
VLDL-Ca
206.5 (110.0, 379.0)
−43.8 (−73.1, −14.3)
LDL-Ca
117.5 (80.0, 170.0)
−40.8 (−63.7, 4.6)
29
Reference ID: 3090896
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Table 9:
Patients with Fredrickson Type III Dysbetalipoproteinemia Median
(min, max) % Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
HDL-C
30.0 (18.0, 88.0)
6.4 (−45.0, 105.6)
Non-HDL-C
344.5 (215.0, 646.0)
−36.7 (−66.3, 5.8)
a N=14
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
−31.4 (−54.5, −13.0)
TG
343.2 (212.6, 845.9)
−11.9 (−56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
−35.7 (−74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
−30.3 (−52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (−17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
−35.5 (−81.0, −13.5)
14.6
Pediatric Clinical Study
A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2
years. The children (aged 8-13 years) were randomized to placebo (N=63) or 20 mg of
pravastatin daily (N=65) and the adolescents (aged 14-18 years) were randomized to placebo
(N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level
>95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of
familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL
in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL) groups,
respectively.
Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children
and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was
similar.
30
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Table 10:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients with
Heterozygous Familial Hypercholesterolemia: Least-Squares Mean %
Change from Baseline at Month 24 (Last Observation Carried
Forward: Intent-to-Treat)a
Pravastatin
20 mg
(Aged 8-13
years)
N=65
Pravastatin
40 mg
(Aged 14-18
years)
N=41
Combined
Pravastatin
(Aged 8-18
years)
N=106
Combined
Placebo
(Aged 8-18
years)
N=108
95% CI of the
Difference Between
Combined
Pravastatin and
Placebo
LDL-C
−26.04b
−21.07b
−24.07b
−1.52
(−26.74, −18.86)
TC
−20.75b
−13.08b
−17.72b
−0.65
(−20.40, −13.83)
HDL-C
1.04
13.71
5.97
3.13
(−1.71, 7.43)
TG
−9.58
−0.30
−5.88
−3.27
(−13.95, 10.01)
ApoB
(N)
−23.16b
(61)
−18.08b
(39)
−21.11b
(100)
−0.97
(106)
(−24.29, −16.18)
a The above least-squares mean values were calculated based on log-transformed lipid values.
b Significant at p≤0.0001 when compared with placebo.
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin group
compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children.
The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
15
REFERENCES
1. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to
mechanisms and disorders. N Engl J Med. 1967;276: 34-44, 94-103, 148-156, 215-225,
273-281.
2. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of
lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol. 1996;10(6):439-446.
3. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study
Group (WOS). Prevention of coronary heart disease with pravastatin in men with
hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
31
Reference ID: 3090896
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. The Long-term Intervention with Pravastatin in Ischemic Disease Group (LIPID). Prevention
of cardiovascular events and death with pravastatin in patients with coronary heart disease
and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
5. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial
Investigators (CARE). The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
6. Pitt B, Mancini GBJ, Ellis SG, et al, for the PLAC I Investigators. Pravastatin limitation of
atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression
and clinical events. J Am Coll Cardiol. 1995;26:1133-1139.
7. Jukema JW, Bruschke AVG, van Boven AJ, et al, for the Regression Growth Evaluation
Statin Study Group (REGRESS). Effects of lipid lowering by pravastatin on progression and
regression of coronary artery disease in symptomatic man with normal to moderately
elevated serum cholesterol levels. Circ. 1995;91:2528-2540.
8. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the
carotid arteries: Design features of a clinical trial with carotid atherosclerosis outcome
(PLAC II). Control Clin Trials. 1992;13:495-506.
9. Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study
(KAPS). A population-based primary preventive trial of the effect of LDL lowering on
atherosclerotic progression in carotid and femoral arteries. Circ. 1995;92:1758-1764.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
PRAVACHOL (pravastatin sodium) Tablets are supplied as:
10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a “P” embossed on
one side and “PRAVACHOL 10” engraved on the opposite side. They are supplied in bottles of
90 (NDC 0003-5154-05). Bottles contain a desiccant canister.
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5178-05). Bottles contain a desiccant canister.
32
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40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5194-10). Bottles contain a desiccant canister.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
They are supplied in bottles of 90 (NDC 0003-5195-10). Bottles contain a desiccant canister.
16.2
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.
17
PATIENT COUNSELING INFORMATION
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1)].
It is recommended that liver enzyme tests be performed before the initiation of PRAVACHOL,
and thereafter when clinically indicated. All patients treated with PRAVACHOL should be
advised to promptly report any symptoms that may indicate liver injury, including fatigue,
anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and
Precautions (5.2)].
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
1292354A0
Rev TBD
33
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|
custom-source
|
2025-02-12T13:46:15.835694
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019898s062lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
11,830
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALTACE safely and effectively. See full prescribing information for
ALTACE.
Altace (ramipril) Capsules, Oral
Initial U.S. Approval: 1991
WARNING: AVOID USE IN PREGNANCY
See full prescribing information for complete boxed warning
When used in pregnancy, ACE inhibitors can cause injury and death
to the developing fetus. When pregnancy is detected, discontinue
ALTACE® as soon as possible (5.6).
----------------------------RECENT MAJOR CHANGES-------------------------
WARNINGS AND PRECAUTIONS
•
Dual Blockade of the Renin-Angiotensin-Aldosterone System:
Telmisartan ( 5.7)
10/2010
----------------------------INDICATIONS AND USAGE---------------------------
•
ALTACE® is indicated for the treatment of hypertension. It may be
used alone or in combination with thiazide diuretics. (1.1).
•
In patients 55 years or older at high risk of developing a major
cardiovascular event, ALTACE is indicated to reduce the risk of
myocardial infarction, stroke, or death from cardiovascular causes
(1.2).
•
ALTACE is indicated in stable patients who have demonstrated
clinical signs of congestive heart failure post-myocardial infarction
(1.3).
----------------------DOSAGE AND ADMINISTRATION-----------------------
•
Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust
dosage according to blood pressure response after 2–4 weeks of
treatment. The usual maintenance dose following titration is 2.5 mg to
20 mg daily as a single dose or equally divided doses (2.1).
•
Reduction in the risk of myocardial infarction, stroke, or death from
cardiovascular causes: 2.5 mg once daily for 1 week, 5 mg once daily
for 3 weeks, and increased as tolerated to a maintenance dose of 10 mg
once daily (2.2).
•
Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice
daily. If patient becomes hypotensive at this dose, decrease dosage to
1.25 mg twice daily. Increase dose as tolerated toward a target dose of
5 mg twice daily, with dosage increases about 3 weeks apart (2.3).
•
Dosage adjustment: See respective sections pertaining to dosage
adjustment in special situations (2.5).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
Angioedema related to previous treatment with an ACE inhibitor, or a history
of hereditary or idiopathic angioedema.(4).
-----------------------WARNINGS AND PRECAUTIONS------------------------
ACE inhibitor use has been associated with the following:
•
Angioedema, with increased risk in patients with a prior history (5.1)
•
Hypotension and hyperkalemia (5.5, 5.8)
•
Renal impairment: monitor renal function during therapy (5.3)
•
Increased risk of renal impairment when combined with another
blocker of the renin-angiotensin-aldosterone system (5.7)
•
Rare cholestatic jaundice and hepatic failure (5.2 )
•
Rare neutropenia and agranulocytosis (5.4)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in patients with hypertension included
headache, dizziness, fatigue, and cough (6.1.1).
To report SUSPECTED ADVERSE REACTIONS, contact King
Pharmaceuticals, Inc. at 1-800-546-4905 or DSP@kingpharm.com or the
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
•
Diuretics: Possibility of excessive hypotension (7.1).
•
Lithium: Use with caution (7.3).
•
Gold: Nitritoid reactions have been reported (7.4).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
•
Pregnancy: Discontinue drug if pregnancy is detected (5.6, 8.1).
•
Nursing mothers: ALTACE use is not recommended in nursing
mothers (8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 10/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: USE IN PREGNANCY
1 INDICATIONS AND USAGE
1.1 Hypertension
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death
from Cardiovascular Causes
1.3 Heart Failure Post-Myocardial Infarction
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
2.3 Heart Failure Post-Myocardial Infarction
2.4 General Dosing Information
2.5 Dosage Adjustment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hepatic Failure and Impaired Liver Function
5.3 Renal Impairment
5.4 Neutropenia and Agranulocytosis
5.5 Hypotension
5.6 Fetal/Neonatal Morbidity and Mortality
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
5.8 Hyperkalemia
5.9 Cough
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
6.3 Clinical Laboratory Test Findings
7 DRUG INTERACTIONS
7.1 Diuretics
7.2 Other Antihypertensive Agents
7.3 Lithium
7.4 Gold
7.5 Other
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism Of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
14 CLINICAL STUDIES
14.1 Hypertension
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
14.3 Heart Failure Post-Myocardial Infarction
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
17.2 Neutropenia
17.3 Symptomatic Hypotension
17.4 Pregnancy
17.5 Hyperkalemia
*Sections or subsections omitted from the full prescribing information are not listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: USE IN PREGNANCY
•
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the
developing fetus. When pregnancy is detected, discontinue ALTACE® as soon as possible (5.6).
1 INDICATIONS AND USAGE
1.1 Hypertension
ALTACE® is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
ALTACE is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a
history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other
cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or
documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes.
ALTACE can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering
therapy) [see Clinical Studies (14.2)].
1.3 Heart Failure Post-Myocardial Infarction
ALTACE is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first
few days after sustaining acute myocardial infarction. Administration of ALTACE to such patients has been shown to
decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and
progression to severe/resistant heart failure [see Clinical Studies (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood
pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in
two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end
of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is
not controlled with ALTACE alone, a diuretic can be added.
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a
maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, ALTACE can
also be given as a divided dose.
2.3 Heart Failure Post-Myocardial Infarction
For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the
recommended starting dose of ALTACE is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this
dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a
target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood
pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may
diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see
Warnings and Precautions (5.5), Drug Interactions (7.1)].
2.4 General Dosing Information
Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a
small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is
not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and
stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing
diuretics can lead to increases of serum potassium [see Warnings and Precautions (5.8)].
2.5 Dosage Adjustment
Renal Impairment
Establish baseline renal function in patients initiating ALTACE Usual regimens of therapy with ALTACE may be
followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25%
of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific Population
(8.6)].
Hypertension
For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily.
Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction
For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily. The
dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical
response and tolerability.
Volume Depletion or Renal Artery Stenosis
Blood pressure decreases associated with any dose of ALTACE depend, in part, on the presence or absence of volume
depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are
suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.
3 DOSAGE FORMS AND STRENGTHS
ALTACE (ramipril) is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.
4 CONTRAINDICATIONS
ALTACE is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient
who has experienced angioedema during therapy with any other ACE inhibitor).
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the
metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including
ALTACE) may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while
receiving an ACE inhibitor
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE
inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, discontinue treatment with ALTACE and institute appropriate therapy immediately. Where
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy
(e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly. [see ADVERSE REACTIONS (6)].
In considering the use of ALTACE, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema
in Black patients than in non-Black patients.
In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was
reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different
statistically.
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal
pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase
levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-
threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were
temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly
with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein
apheresis with dextran sulfate absorption.
5.2 Hepatic Failure and Impaired Liver Function
Rarely, ACE inhibitors, including ALTACE, have been associated with a syndrome that starts with cholestatic jaundice
and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood.
Discontinue ALTACE if patient develops jaundice or marked elevations of hepatic enzymes.
As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver
function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been
carried out in hypertensive patients with impaired liver function.
5.3 Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in
susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity
of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ALTACE, may be associated with
oliguria or progressive azotemia and rarely with acute renal failure or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum
creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon
discontinuation of ALTACE and/or diuretic therapy. In such patients, monitor renal function during the first few weeks
of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in
blood urea nitrogen and serum creatinine, usually minor and transient, especially when ALTACE has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage
reduction of ALTACE and/or discontinuation of the diuretic may be required.
5.4 Neutropenia and Agranulocytosis
In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and
hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow
depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-
vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white
blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal
function.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.5 Hypotension
General Considerations
ALTACE can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been
increased. Like other ACE inhibitors, ALTACE, has been only rarely associated with hypotension in uncomplicated
hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-
depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume-
and salt-depletion before initiating therapy with ALTACE.
If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of
physiological saline. ALTACE treatment usually can be continued following restoration of blood pressure and volume.
Heart Failure Post-Myocardial Infarction
In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of ALTACE. If the initial dose of 2.5 mg ALTACE cannot
be tolerated, use an initial dose of 1.25 mg ALTACE to avoid excessive hypotension. Consider reducing the dose of
concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause
excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.
In such patients, initiate ALTACE therapy under close medical supervision and follow patients closely for the first 2
weeks of treatment and whenever the dose of ALTACE or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin
II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of
this mechanism can be corrected by volume expansion.
5.6 Fetal/Neonatal Morbidity and Mortality
Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to
pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected,
discontinue ACE inhibitors as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal
injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.
Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in
this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were caused by the ACE inhibitor exposure.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first
trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants
whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is
small and the findings of this study have not yet been confirmed.
Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin
aldosterone system will be found. In these rare cases, inform mothers about the potential hazards to their fetuses, and
perform serial ultrasound examinations to assess the intraamniotic environment.
If oligohydramnios is observed, discontinue ALTACE unless it is considered life-saving for the mother. Contraction
stress testing, a nonstress test, or biophysical profiling may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained
irreversible injury.
Closely observe infants with histories of in utero exposure to ACE inhibitors for hypotension, oliguria, and hyperkalemia.
If oliguria occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusion or dialysis
may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which
crosses the placenta, can be removed from the neonatal circulation by these means, but limited experience has not shown
that such removal is central to the treatment of these infants.
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5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Telmisartan
The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ
damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56
months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite
endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced
an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis)
compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not
recommended.
5.8 Hyperkalemia
In clinical trials with ALTACE, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of
hypertensive patients receiving ALTACE. In most cases, these were isolated values, which resolved despite continued
therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing
diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all,
with ALTACE [see Drug Interactions (7.1)].
5.9 Cough
Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been
reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of
angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Hypertension
ALTACE has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in
U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at
least one year. The overall incidence of reported adverse events was similar in ALTACE and placebo patients. The most
frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ALTACE in
placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one
was more common in ALTACE patients than in patients given placebo. Generally the side effects were mild and transient,
and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side
effect was required in approximately 3% of U.S. patients treated with ALTACE. The most common reasons for
discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).
Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled
trials in more than 1% of patients treated with ALTACE, only asthenia (fatigue) was more common on ALTACE than
placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).
In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ALTACE
group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE
inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased
cough was seen in almost 12% of ALTACE patients, with about 4% of patients requiring discontinuation of treatment.
Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
HOPE Study
Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or
temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril
Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials [see Warnings and Precautions
(5.1)].
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Table 1. Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study
Placebo
(N=4652)
ALTACE
(N=4645)
Discontinuation at any time
32%
34%
Permanent discontinuation
28%
29%
Reasons for stopping
Cough
2%
7%
Hypotension or dizziness
1.5%
1.9%
Angioedema
0.1%
0.3%
Heart Failure Post-Myocardial Infarction
AIRE Study
Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in
more than 1% of patients and more frequently on ALTACE are shown below. The incidences are from the AIRE study.
The follow-up time was between 6 and 46 months for this study.
Table 2. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-
Controlled (AIRE) Mortality Study
Adverse Event
Placebo
(N=982)
ALTACE
(N=1004)
Hypotension
5%
11%
Cough increased
4%
8%
Dizziness
3%
4%
Angina pectoris
2%
3%
Nausea
1%
2%
Postural hypotension
1%
2%
Syncope
1%
2%
Vomiting
0.5%
2%
Vertigo
0.7%
2%
Abnormal kidney function
0.5%
1%
Diarrhea
0.4%
1%
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of ALTACE patients), or rarer events seen in
post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Body as a whole: Anaphylactoid reactions [see Warnings and Precautions (5.1)].
Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see Warnings and Precautions
(5.5)], syncope, and palpitations.
Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.
Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in
0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic.
Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor,
usually transient, increases in blood urea nitrogen and serum creatinine when taking ALTACE, particularly when
ALTACE was given concomitantly with a diuretic [see Warnings and Precautions (5.3)].
Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ALTACE [see
Warnings and Precautions (5.1)].
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Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes
suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased
salivation, and taste disturbance.
Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever),
photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and
Stevens-Johnson syndrome.
Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia,
neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA,
an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity,
rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has
been reported.
Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.
6.2 Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during
ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal
relationship is unknown.
6.3 Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE
alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5%
of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases
required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal
insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to
be especially likely in patients with renal artery stenosis [see Warnings and Precautions (5.3)]. As ramipril decreases
aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing
diuretics with caution, and monitor the patient’s serum potassium frequently [see Warnings and Precautions (5.8)].
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%,
respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving
ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated
with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been
reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials,
less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or
abnormal liver-function tests.
7 DRUG INTERACTIONS
7.1 DIURETICS
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an
excessive reduction of blood pressure after initiation of therapy with ALTACE. The possibility of hypotensive effects
with ALTACE can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to
initiation of treatment with ALTACE. If this is not possible, reduce the starting dose [see DOSAGE AND
ADMINISTRATION (2)].
ALTACE can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if
concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.
7.2 Other Antihypertensive Agents
Limited experience in controlled and uncontrolled trials combining ALTACE with a calcium channel blocker, a loop
diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE
inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower
blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
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The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart
rate).
In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased
incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups
receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended. [see Dual
Blockade of the Renin-Angiotensin-Aldosterone System (5.7)].
7.3 Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors
during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also
used, the risk of lithium toxicity may be increased.
7.4 Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in
patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including
ALTACE.
7.5 Other
Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine,
indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation
effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum
phenprocoumon levels or interfere with the patients’ state of anticoagulation.
Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with
worsening of renal failure and an increase in serum potassium.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters) [see Warnings and Precautions (5.6)].
8.3 Nursing Mothers
Ingestion of a single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in
breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single
dose, do not use ALTACE in nursing mothers.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in
very young rats given a single dose of ALTACE.
8.5 Geriatric Use
Of the total number of patients who received ALTACE in U.S. clinical studies of ALTACE, 11.0% were ≥65 years of age
while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients
and younger patients, and other reported clinical experience has not identified differences in responses between the elderly
and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under
the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
8.6 Renal Impairment
A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment
who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of
creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and
severe impairment (<15 mL/min). On average, the AUC0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold
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higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the
group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted
downward in patients with moderate-to-severe renal impairment.
10 OVERDOSAGE
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as
high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most
likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might
accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be
effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but
angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril
is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of
normal saline solution.
11 DESCRIPTION
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar
organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3
phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell
contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell
contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is: structural formula
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by
hepatic cleavage of the ester group.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl
dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II
also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II,
which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up
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to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from
baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline
greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide
for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and
approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see Warnings and
Precautions (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity.
The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE
activity, thereby reducing angiotensin II formation in tissue and plasma.
Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated.
While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the renin-
angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension.
Although ALTACE was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin
hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than
non-Black patients.
12.2 Pharmacodynamics
Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after
dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause
plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining
24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE
binding sites by ramiprilat and relatively slow release from those sites.
12.3 Pharmacokinetics
Absorption
Following oral administration of ALTACE, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The
extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal
tract, although the rate of absorption is reduced.
In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved
in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the
concomitant liquid or food.
Distribution
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak
plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is
about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of
0.01 µg/mL–10 µg/mL.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril,
and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which
are inactive.
Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The
24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg-20 mg dose range. The absolute
bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared
with the same dose of ramipril given intravenously.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state
concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses
(2.5 mg), but the difference is clinically insignificant.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase,
terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral
compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent
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binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent
elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal
elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the
ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ALTACE
5 mg-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and
trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these
patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of
diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak
concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic
function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
Excretion
After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and
about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or
unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the
administered dose is recovered in urine as unchanged ramipril.
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function.
Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough
ramiprilat levels and slightly longer times to peak concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of
up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are
about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No
mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in
a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and
degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as
500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body
surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the
recommended human dose.
14 CLINICAL STUDIES
14.1 Hypertension
ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for
hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and
standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is
infrequent, although it can occur in patients who are salt- and/or volume-depleted [see Warnings and Precautions (5.5)].
Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with
either agent alone.
In single-dose studies, doses of 5 mg–20 mg of ALTACE lowered blood pressure within 1–2 hours, with peak reductions
achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12
weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing
systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of
peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titration study comparing
divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive
effect with once-daily dosing is not adequately maintained.
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In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements.
The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt
withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other
ACE inhibitors, beta-blockers, and thiazide diuretics. ALTACE was approximately as effective as other ACE inhibitors
and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than
ramipril.
ALTACE was less effective in blacks than in Caucasians. The effectiveness of ALTACE was not influenced by age, sex,
or weight.
In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied
by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial design study
conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a
major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes
that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low
HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment
with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low
ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg
orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction,
stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3
components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to
the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of
treatment.
Table 3. Summary of Combined Components and Endpoints—HOPE Study
Outcome
Placebo
(N=4652)
n (%)
ALTACE
(N=4645)
n (%)
Relative Risk
(95% CI)
P-Value
Combined Endpoint
Myocardial infarction,
stroke, or death from
cardiovascular cause
826 (17.8%)
651 (14.0%)
0.78 (0.70–0.86)
P=0.0001
Component Endpoint
Death from cardiovascular
causes
377 (8.1%)
282 (6.1%)
0.74 (0.64–0.87)
P=0.0002
Myocardial infarction
570 (12.3%)
459 (9.9%)
0.80 (0.70–0.90)
P=0.0003
Stroke
226 (4.9%)
156 (3.4%)
0.68 (0.56–0.84)
P=0.0002
Overall Mortality
Death from any cause
569 (12.2%)
482 (10.4%)
0.84 (0.75–0.95)
P=0.005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from
Cardiovascular Causes in the Ramipril Group and the Placebo Group graph
ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease
(e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient
data to determine whether or not ALTACE was equally effective in ethnic subgroups.
This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor.
Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to those in the
overall study population.
Table 4. Summary of Combined Endpoints and Components in Diabetics—HOPE Study
Outcome
Placebo
(N=1769)
n (%)
ALTACE
(N=1808)
n (%)
Relative Risk
Reduction
(95% CI)
P-value
Combined Endpoint
Myocardial infarction,
stroke, or death from
cardiovascular cause
351 (19.8%)
277 (15.3%)
0.25 (0.12–0.36)
P=0.0004
Component Endpoint
Death from cardiovascular
causes
172 (9.7%)
112 (6.2%)
0.37 (0.21–0.51)
P=0.0001
Myocardial infarction
229 (12.9%)
185 (10.2%)
0.22 (0.06–0.36)
P=0.01
Stroke
108 (6.1%)
76 (4.2%)
0.33 (0.10–0.50)
P=0.007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2. The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction,
Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups graph
Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the
number of patients in each group. The dashed line indicates overall relative risk.
The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, beta-
blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
14.3 Heart Failure Post-Myocardial Infarction
ALTACE was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-
blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2–9 days after an acute
myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction.
Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or
valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had
received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of
treatment was 5 days.
Patients randomized to ALTACE treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused
undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a
target regimen (achieved in 77% of patients randomized to ALTACE) of 5 mg twice daily. Patients were then followed
for an average of 15 months, with the range of follow-up between 6 and 46 months.
The use of ALTACE was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of
the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of
congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively.
The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the
initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in
patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80%
of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers
(about 15%), and digoxin (about 12%).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
ALTACE is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules. Descriptions of ALTACE capsules are
summarized below.
Capsule
Strength
Capsule Color
Package
Configuration
NDC#
1.25 mg
yellow
Bottle of 100
61570-110-01
2.5 mg
orange
Bottle of 100
61570-111-01
Bottle of 500
61570-111-05
Unit Dose Pack of
100
61570-111-56
Bulk Pack of 5000
61570-111-50
5 mg
red
Bottle of 100
61570-112-01
Bottle of 500
61570-112-05
Unit Dose Pack of
100
61570-112-56
Bulk Pack of 5000
61570-112-50
10 mg
Process Blue
Bottle of 100
61570-120-01
Bottle of 500
61570-120-05
Dispense in well-closed container with safety closure.
Store at controlled room temperature (59º–86ºF).
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the
first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes,
lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing
physician.
17.2 Neutropenia
Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of
neutropenia.
17.3 Symptomatic Hypotension
Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported.
Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can
lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
17.4 Pregnancy
Inform female patients of childbearing age about the consequences of exposure to ACE inhibitors during pregnancy.
Advise these patients to report pregnancies to their physicians as soon as possible.
17.5 Hyperkalemia
Advise patients not to use salt substitutes containing potassium without consulting their physician.
Distributed by:
Monarch Pharmaceuticals, Inc.
Bristol, TN 37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
King Pharmaceuticals, Inc.
Bristol, TN 37620
Label Code # 60793
Revised: 10/2010
King Pharmaceuticals, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:15.966010
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019901s055lbl.pdf', 'application_number': 19901, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
11,829
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRAVACHOL safely and effectively. See full prescribing information for
PRAVACHOL.
PRAVACHOL (pravastatin sodium) Tablets
Initial U.S. Approval: 1991
----------------------------RECENT MAJOR CHANGES--------------------------
Dosage and Administration
Patients with Renal Impairment (2.3)
7/2016
Contraindications
Pregnancy (4.3), Lactation (4.4)
7/2016
-----------------------------INDICATIONS AND USAGE-----------------------------
PRAVACHOL is an HMG-CoA reductase inhibitor (statin) indicated as an
adjunctive therapy to diet to:
• Reduce the risk of MI, revascularization, and cardiovascular mortality in
hypercholesterolemic patients without clinically evident CHD. (1.1)
• Reduce the risk of total mortality by reducing coronary death, MI,
revascularization, stroke/TIA, and the progression of coronary atherosclerosis
in patients with clinically evident CHD. (1.1)
• Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL
C in patients with primary hypercholesterolemia and mixed dyslipidemia.
(1.2)
• Reduce elevated serum TG levels in patients with hypertriglyceridemia. (1.2)
• Treat patients with primary dysbetalipoproteinemia who are not responding to
diet. (1.2)
• Treat children and adolescent patients ages 8 years and older with
heterozygous familial hypercholesterolemia after failing an adequate trial of
diet therapy. (1.2)
Limitations of use:
• PRAVACHOL has not been studied in Fredrickson Types I and V
dyslipidemias. (1.3)
-----------------------------DOSAGE AND ADMINISTRATION-------------------
• Adults: the recommended starting dose is 40 mg once daily. Use 80 mg dose
only for patients not reaching LDL-C goal with 40 mg. (2.2)
• Significant renal impairment: the recommended starting dose is pravastatin 10
mg once daily. (2.3)
• Children (ages 8 to 13 years, inclusive): the recommended starting dose is
20 mg once daily. (2.4)
• Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg
once daily. (2.4)
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Prevention of Cardiovascular Disease
1.2
Hyperlipidemia
1.3
Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
2.2
Adult Patients
2.3
Patients with Renal Impairment
2.4
Pediatric Patients
2.5
Concomitant Lipid-Altering Therapy
2.6
Dosage in Patients Taking Cyclosporine
2.7
Dosage in Patients Taking Clarithromycin
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Hypersensitivity
4.2
Liver
4.3
Pregnancy
4.4
Lactation
5
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle
5.2
Liver
5.3
Endocrine Function
6
ADVERSE REACTIONS
6.1
Adverse Clinical Events
6.2
Postmarketing Experience
6.3
Laboratory Test Abnormalities
6.4
Pediatric Patients
7
DRUG INTERACTIONS
7.1
Cyclosporine
7.2
Clarithromycin and Other Macrolide Antibiotics
7.3
Colchicine
7.4
Gemfibrozil
7.5
Other Fibrates
---------------------------DOSAGE FORMS AND STRENGTHS-------------------
• Tablets: 20 mg, 40 mg, 80 mg. (3)
--------------------------------CONTRAINDICATIONS-------------------------------
• Hypersensitivity to any component of this medication. (4.1, 6.2, 11)
• Active liver disease or unexplained, persistent elevations of serum
transaminases. (4.2, 5.2)
• Pregnancy (4.3, 8.1, 8.3)
• Lactation (4.4, 8.2)
----------------------------WARNINGS AND PRECAUTIONS----------------------
• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing
factors include advanced age (≥65), uncontrolled hypothyroidism, and renal
impairment. Patients should be advised to promptly report to their physician
any unexplained and/or persistent muscle pain, tenderness, or weakness.
Pravastatin therapy should be discontinued if myopathy is diagnosed or
suspected. (5.1, 8.5)
• Liver enzyme abnormalities: persistent elevations in hepatic transaminases
can occur. Check liver enzyme tests before initiating therapy and as clinically
indicated thereafter. (5.2)
-----------------------------------ADVERSE REACTIONS-----------------------------
In short-term clinical trials, the most commonly reported adverse reactions (≥2%
and > placebo) regardless of causality were: musculoskeletal pain,
nausea/vomiting, upper respiratory infection, diarrhea, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------------DRUG INTERACTIONS----------------------------
• Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying
doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle
effects. Caution should be used when prescribing with PRAVACHOL. (7)
• Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg
once daily. (2.6, 7.1)
• Clarithromycin: combination increases exposure. Limit pravastatin to 40 mg
once daily. (2.7, 7.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 7/2016
7.6
Niacin
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Homozygous Familial Hypercholesterolemia
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Prevention of Coronary Heart Disease
14.2
Secondary Prevention of Cardiovascular Events
14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and
IIb)
14.4
Hypertriglyceridemia (Fredrickson Type IV)
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
14.6
Pediatric Clinical Study
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
Reference ID: 3954762
1
1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor
intervention in individuals at significantly increased risk for atherosclerotic vascular disease due
to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a
diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has
been inadequate.
1.1
Prevention of Cardiovascular Disease
In hypercholesterolemic patients without clinically evident coronary heart disease (CHD),
PRAVACHOL (pravastatin sodium) is indicated to:
• reduce the risk of myocardial infarction (MI).
• reduce the risk of undergoing myocardial revascularization procedures.
• reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular
causes.
In patients with clinically evident CHD, PRAVACHOL is indicated to:
• reduce the risk of total mortality by reducing coronary death.
• reduce the risk of MI.
• reduce the risk of undergoing myocardial revascularization procedures.
• reduce the risk of stroke and stroke/transient ischemic attack (TIA).
• slow the progression of coronary atherosclerosis.
1.2
Hyperlipidemia
PRAVACHOL is indicated:
• as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase
high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia
and mixed dyslipidemia (Fredrickson Types IIa and IIb).1
• as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson
Type IV).
• for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III)
who do not respond adequately to diet.
Reference ID: 3954762
2
• as an adjunct to diet and lifestyle modification for treatment of heterozygous familial
hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if
after an adequate trial of diet the following findings are present:
a. LDL-C remains ≥190 mg/dL or
b. LDL-C remains ≥160 mg/dL and:
• there is a positive family history of premature cardiovascular disease (CVD) or
• two or more other CVD risk factors are present in the patient.
1.3
Limitations of Use
PRAVACHOL has not been studied in conditions where the major lipoprotein abnormality is
elevation of chylomicrons (Fredrickson Types I and V).
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
The patient should be placed on a standard cholesterol-lowering diet before receiving
PRAVACHOL and should continue on this diet during treatment with PRAVACHOL [see
NCEP Treatment Guidelines for details on dietary therapy].
2.2
Adult Patients
The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve
desired cholesterol levels, 80 mg once daily is recommended. PRAVACHOL can be
administered orally as a single dose at any time of the day, with or without food. Since the
maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be
performed at this time and dosage adjusted according to the patient’s response to therapy and
established treatment guidelines.
2.3
Patients with Renal Impairment
In patients with severe renal impairment, a starting dose of 10 mg pravastatin daily is
recommended. Although the PRAVACHOL 10 mg tablets are no longer available, pravastatin
10 mg tablets are available.
Reference ID: 3954762
3
2.4
Pediatric Patients
Children (Ages 8 to 13 Years, Inclusive)
The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than
20 mg have not been studied in this patient population.
Adolescents (Ages 14 to 18 Years)
The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses
greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be reevaluated in adulthood and
appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for
LDL-C [see Indications and Usage (1.2)].
2.5
Concomitant Lipid-Altering Therapy
PRAVACHOL may be used with bile acid resins. When administering a bile-acid-binding resin
(e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given either 1 hour
or more before or at least 4 hours following the resin. [See Clinical Pharmacology (12.3).]
2.6
Dosage in Patients Taking Cyclosporine
In patients taking immunosuppressive drugs such as cyclosporine concomitantly with
pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and
titration to higher doses should be done with caution. Most patients treated with this combination
received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine,
therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and
Precautions (5.1) and Drug Interactions (7.1)]. Although the PRAVACHOL 10 mg tablets are
no longer available, pravastatin 10 mg tablets are available.
2.7
Dosage in Patients Taking Clarithromycin
In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once
daily [see Drug Interactions (7.2)].
Reference ID: 3954762
4
3
DOSAGE FORMS AND STRENGTHS
PRAVACHOL Tablets are supplied as:
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side.
80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
4
CONTRAINDICATIONS
4.1
Hypersensitivity
Hypersensitivity to any component of this medication.
4.2
Liver
Active liver disease or unexplained, persistent elevations of serum transaminases [see Warnings
and Precautions (5.2)].
4.3
Pregnancy
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
components for fetal development (including synthesis of steroids and cell membranes). Since
statins decrease cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, they are contraindicated during pregnancy and in nursing
mothers.
PRAVASTATIN
SHOULD
BE
ADMINISTERED
TO
WOMEN
OF
CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO
CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient
becomes pregnant while taking this class of drug, therapy should be discontinued immediately
and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1,
8.3)].
Reference ID: 3954762
5
5
4.4
Lactation
Pravastatin is present in human milk. Because statins have the potential for serious adverse
reactions in nursing infants, women who require PRAVACHOL treatment should not breastfeed
their infants [see Use in Specific Populations (8.2)].
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have
been reported with pravastatin and other drugs in this class. A history of renal impairment
may be a risk factor for the development of rhabdomyolysis. Such patients merit closer
monitoring for skeletal muscle effects.
Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse
Reactions (6)]. Myopathy, defined as muscle aching or muscle weakness in conjunction with
increases in creatine phosphokinase (CPK) values to greater than 10 times the ULN, was rare
(<0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse
myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Predisposing factors
include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an
autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle
weakness and elevated serum CPK, which persist despite discontinuation of statin treatment;
muscle biopsy showing necrotizing myopathy without significant inflammation and
improvement with immunosuppressive agents.
All patients should be advised to promptly report to their physician unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and
symptoms persist after discontinuing PRAVACHOL.
Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or
myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily
withheld in any patient experiencing an acute or serious condition predisposing to the
development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major
Reference ID: 3954762
6
surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled
epilepsy.
The risk of myopathy during treatment with statins is increased with concurrent therapy with
either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant
increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant
patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to
40 mg and cyclosporine. Some of these patients also received other concomitant
immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who
were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also,
myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil
(1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations
versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK
elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving
combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin
monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The
benefit of further alterations in lipid levels by the combined use of PRAVACHOL with
fibrates should be carefully weighed against the potential risks of this combination.
Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin
coadministered with colchicine, and caution should be exercised when prescribing pravastatin
with colchicine [see Drug Interactions (7.3)].
5.2
Liver
Statins, like some other lipid-lowering therapies, have been associated with biochemical
abnormalities of liver function. In 3 long-term (4.8-5.9 years), placebo-controlled clinical trials
(WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or
placebo [see Clinical Studies (14)]. In an analysis of serum transaminase values (ALT, AST),
incidences of marked abnormalities were compared between the pravastatin and placebo
treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3
times the ULN for subjects with pretreatment values less than or equal to the ULN, or 4 times the
pretreatment value for subjects with pretreatment values greater than the ULN but less than 1.5
times the ULN. Marked abnormalities of ALT or AST occurred with similar low frequency
(≤1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function
test abnormalities observed during pravastatin therapy were usually asymptomatic, not
associated with cholestasis, and did not appear to be related to treatment duration. In a 320
Reference ID: 3954762
7
patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease,
due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg
pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of
subjects with at least one ALT ≥2 times the ULN for those with normal ALT (≤ ULN) at
baseline or a doubling of the baseline ALT for those with elevated ALT (> ULN) at baseline. By
Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT
endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding
liver safety are limited since the study was not large enough to establish similarity between
groups (with 95% confidence) in the rates of ALT elevation.
It is recommended that liver function tests be performed prior to the initiation of therapy
and when clinically indicated.
Active liver disease or unexplained persistent transaminase elevations are contraindications to
the use of pravastatin [see Contraindications (4.2)]. Caution should be exercised when
pravastatin is administered to patients who have a recent (<6 months) history of liver disease,
have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations,
jaundice), or are heavy users of alcohol.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients
taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment with PRAVACHOL, promptly interrupt
therapy. If an alternate etiology is not found do not restart PRAVACHOL.
5.3
Endocrine Function
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such,
might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials
with pravastatin in males and post-menopausal females were inconsistent with regard to possible
effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone
response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of
treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in
plasma testosterone after human chorionic gonadotropin stimulation did not change significantly
after therapy in these patients. The effects of statins on spermatogenesis and fertility have not
been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-
gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who
display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution
Reference ID: 3954762
8
should also be exercised if a statin or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may
diminish the levels or activity of steroid hormones.
In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated
with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18
years) for 2 years, there were no detectable differences seen in any of the endocrine parameters
(ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to
placebo. There were no detectable differences seen in height and weight changes, testicular
volume changes, or Tanner score relative to placebo.
6
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In
4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of
placebo-treated patients were discontinued from treatment because of adverse experiences
attributed to study drug therapy; this difference was not statistically significant.
6.1
Adverse Clinical Events
Short-Term Controlled Trials
In the PRAVACHOL placebo-controlled clinical trials database of 1313 patients (age range
20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2%
Others) with a median treatment duration of 14 weeks, 3.3% of patients on PRAVACHOL and
1.2% patients on placebo discontinued due to adverse events regardless of causality. The most
common adverse reactions that led to treatment discontinuation and occurred at an incidence
greater than placebo were: liver function test increased, nausea, anxiety/depression, and
dizziness.
All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated
patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:
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Table 1:
Adverse Events in ≥2% of Patients Treated with Pravastatin 5 to
40 mg and at an Incidence Greater Than Placebo in Short-Term
Placebo-Controlled Trials (% of patients)
Body System/Event
5 mg
N=100
10 mg
N=153
20 mg
N=478
40 mg
N=171
Any Dose
N=902
Placebo
N=411
Cardiovascular
Angina Pectoris
5.0
4.6
4.8
3.5
4.5
3.4
Dermatologic
Rash
3.0
2.6
6.7
1.2
4.5
1.4
Gastrointestinal
Nausea/Vomiting
4.0
5.9
10.5
2.3
7.4
7.1
Diarrhea
8.0
8.5
6.5
4.7
6.7
5.6
Flatulence
2.0
3.3
4.6
0.0
3.2
4.4
Dyspepsia/Heartburn
0.0
3.3
3.6
0.6
2.5
2.7
Abdominal Distension
2.0
3.3
2.1
0.6
2.0
2.4
General
Fatigue
4.0
1.3
5.2
0.0
3.4
3.9
Chest Pain
4.0
1.3
3.3
1.2
2.7
1.9
Influenza
4.0
2.6
1.9
0.6
2.0
0.7
Musculoskeletal
Musculoskeletal Pain
Myalgia
13.0
1.0
3.9
2.6
13.2
2.9
5.3
1.2
10.1
2.3
10.2
1.2
Nervous System
Headache
Dizziness
5.0
4.0
6.5
1.3
7.5
5.2
3.5
0.6
6.3
3.5
4.6
3.4
Respiratory
Pharyngitis
2.0
4.6
1.5
1.2
2.0
2.7
Upper Respiratory Infection
6.0
9.8
5.2
4.1
5.9
5.8
Rhinitis
7.0
5.2
3.8
1.2
3.9
4.9
Cough
4.0
1.3
3.1
1.2
2.5
1.7
Investigation
ALT Increased
2.0
2.0
4.0
1.2
2.9
1.2
g-GT Increased
3.0
2.6
2.1
0.6
2.0
1.2
CPK Increased
5.0
1.3
5.2
2.9
4.1
3.6
The safety and tolerability of PRAVACHOL at a dose of 80 mg in 2 controlled trials with a
mean exposure of 8.6 months was similar to that of PRAVACHOL at lower doses except that 4
out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN
compared to 0 out of 115 patients taking 40 mg of pravastatin.
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Long-Term Controlled Morbidity and Mortality Trials
In the PRAVACHOL placebo-controlled clinical trials database of 21,483 patients (age range
24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians,
0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of
patients on PRAVACHOL and 9.3% patients on placebo discontinued due to adverse events
regardless of causality.
Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland
Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term
Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of
Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis
in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and
Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated
with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability
profile in the pravastatin group was comparable to that of the placebo group. Patients were
exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9
years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common
reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively,
these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse
events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these
studies are identified in Table 2.
Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Dermatologic
Rash (including dermatitis)
7.2
7.1
General
Edema
Fatigue
Chest Pain
Fever
Weight Gain
Weight Loss
3.0
8.4
10.0
2.1
3.8
3.3
2.7
7.8
9.8
1.9
3.3
2.8
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Table 2:
Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg
and at an Incidence Greater Than Placebo in Long-Term Placebo-
Controlled Trials
Body System/Event
Pravastatin
(N=10,764)
% of patients
Placebo
(N=10,719)
% of patients
Musculoskeletal
Musculoskeletal Pain
Muscle Cramp
Musculoskeletal Traumatism
24.9
5.1
10.2
24.4
4.6
9.6
Nervous System
Dizziness
Sleep Disturbance
Anxiety/Nervousness
Paresthesia
7.3
3.0
4.8
3.2
6.6
2.4
4.7
3.0
Renal/Genitourinary
Urinary Tract Infection
2.7
2.6
Respiratory
Upper Respiratory Tract Infection
Cough
Influenza
Pulmonary Infection
Sinus Abnormality
Tracheobronchitis
21.2
8.2
9.2
3.8
7.0
3.4
20.2
7.4
9.0
3.5
6.7
3.1
Special Senses
Vision Disturbance (includes blurred vision, diplopia)
3.4
3.3
Infections
Viral Infection
3.2
2.9
In addition to the events listed above in the long-term trials table, events of probable, possible, or
uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the
long-term trials included the following:
Dermatologic: scalp hair abnormality (including alopecia), urticaria.
Endocrine/Metabolic: sexual dysfunction, libido change.
General: flushing.
Immunologic: allergy, edema head/neck.
Musculoskeletal: muscle weakness.
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Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral
neuropathy).
Special Senses: taste disturbance.
6.2
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following events
have been reported during postmarketing experience with PRAVACHOL, regardless of causality
assessment:
Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin
use [see Warnings and Precautions (5.1)].
Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment
of extraocular movement, facial paresis), peripheral nerve palsy.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These
cognitive issues have been reported for all statins. The reports are generally nonserious, and
reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and
symptom resolution (median of 3 weeks).
Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR
increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal
necrolysis, erythema multiforme (including Stevens-Johnson syndrome).
Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active
hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis,
hepatoma, fatal and non-fatal hepatic failure.
Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous
membranes, changes to hair/nails).
Renal: urinary abnormality (including dysuria, frequency, nocturia).
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Respiratory: dyspnea, interstitial lung disease.
Psychiatric: nightmare.
Reproductive: gynecomastia.
Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.
6.3
Laboratory Test Abnormalities
Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions
(5.1, 5.2)].
Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to
normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been
reported with statins.
6.4
Pediatric Patients
In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH
(n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1%
Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.
[See Warnings and Precautions (5.3), Use in Specific Populations (8.4), and Clinical
Pharmacology (12.3).]
7
DRUG INTERACTIONS
For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or
erythromycin, the risk of myopathy increases [see Warnings and Precautions (5.1) and
Clinical Pharmacology (12.3)].
7.1
Cyclosporine
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see
Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology
(12.3)].
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7.2
Clarithromycin and Other Macrolide Antibiotics
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of
clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin
[see Dosage and Administration (2.7), Warnings and Precautions (5.1), and Clinical
Pharmacology (12.3)].
Other macrolides (e.g., erythromycin and azithromycin) have the potential to increase statin
exposures while used in combination. Pravastatin should be used cautiously with macrolide
antibiotics due to a potential increased risk of myopathies.
7.3
Colchicine
The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine
[see Warnings and Precautions (5.1)].
7.4
Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are
coadministered with gemfibrozil, concomitant administration of PRAVACHOL with gemfibrozil
should be avoided [see Warnings and Precautions (5.1)].
7.5
Other Fibrates
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase
inhibitors is increased with concurrent administration of other fibrates, PRAVACHOL should be
administered with caution when used concomitantly with other fibrates [see Warnings and
Precautions (5.1)].
7.6
Niacin
The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination
with niacin; a reduction in PRAVACHOL dosage should be considered in this setting [see
Warnings and Precautions (5.1)].
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8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
PRAVACHOL is contraindicated for use in pregnant woman because of the potential for fetal
harm. As safety in pregnant women has not been established and there is no apparent benefit to
therapy with PRAVACHOL during pregnancy, PRAVACHOL should be immediately
discontinued as soon as pregnancy is recognized [see Contraindications (4.3)]. Limited
published data on the use of PRAVACHOL in pregnant women are insufficient to determine a
drug-associated risk of major congenital malformations or miscarriage. In animal reproduction
studies, no evidence of fetal malformations was seen in rabbits or rats exposed to 10 times to 120
times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day. Fetal
skeletal abnormalities, offspring mortality, and developmental delays occurred when pregnant
rats were administered 10 times to 12 times the MRHD during organogenesis to parturition [see
Data]. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Human Data
Limited published data on pravastatin have not shown an increased risk of major congenital
malformations or miscarriage.
Rare reports of congenital anomalies have been received following intrauterine exposure to other
statins. In a review2 of approximately 100 prospectively followed pregnancies in women
exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous
abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed pregnancies,
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drug treatment was initiated prior to pregnancy and was discontinued at some point in the first
trimester when pregnancy was identified.
Animal Data
Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of
organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral
gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17
(organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies
were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day
MRHD based on body surface area (mg/m2).
In other studies, no teratogenic effects were observed when pravastatin was dosed orally during
organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation
days 7 through 17) up to 1000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat)
the human exposure at 80 mg/day MRHD based on body surface area (mg/m2).
In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17
through lactation day 21 (weaning), increased mortality of offspring and developmental delays
were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human
exposure at 80 mg/day MRHD, based on body surface area (mg/m2).
In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the
maternal plasma levels following administration of a single dose of 20 mg/day orally on
gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on
body surface area (mg/m2). In lactating rats, up to 7 times higher levels of pravastatin are present
in the breast milk than in the maternal plasma, which corresponds to exposure 2 times the
MRHD of 80 mg/day based on body surface area (mg/m2).
8.2
Lactation
Risk Summary
Pravastatin use is contraindicated during breastfeeding [see Contraindications (4.4)]. Based on
one lactation study in published literature, pravastatin is present in human milk. There is no
available information on the effects of the drug on the breastfed infant or the effects of the drug
on milk production. Because of the potential for serious adverse reactions in a breastfed infant,
advise patients that breastfeeding is not recommended during treatment with PRAVACHOL.
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8.3
Females and Males of Reproductive Potential
Contraception
Females
PRAVACHOL may cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females of reproductive potential to use effective
contraception during treatment with PRAVACHOL.
8.4
Pediatric Use
The safety and effectiveness of PRAVACHOL in children and adolescents from 8 to 18 years of
age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with
pravastatin had an adverse experience profile generally similar to that of patients treated with
placebo with influenza and headache commonly reported in both treatment groups. [See Adverse
Reactions (6.4).] Doses greater than 40 mg have not been studied in this population.
Children and adolescent females of childbearing potential should be counseled on appropriate
contraceptive methods while on pravastatin therapy [see Contraindications (4.3) and Use in
Specific Populations (8.1)]. For dosing information [see Dosage and Administration (2.4)].
Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not
been conducted.
8.5
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593
subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies,
36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The
beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in
modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in
the elderly was similar to that in the overall population. Other reported clinical experience has
not identified differences in responses to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25%-50%) higher in elderly subjects than in healthy young
subjects, but mean maximum plasma concentration (Cmax ), time to maximum plasma
concentration (T max ), and half-life (t½) values are similar in both age groups and substantial
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accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology
(12.3)].
Since advanced age (≥65 years) is a predisposing factor for myopathy, PRAVACHOL should be
prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
8.6
Homozygous Familial Hypercholesterolemia
Pravastatin
has
not
been
evaluated
in
patients
with
rare
homozygous
familial
hypercholesterolemia. In this group of patients, it has been reported that statins are less effective
because the patients lack functional LDL receptors.
10
OVERDOSAGE
To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs,
it should be treated symptomatically with laboratory monitoring and supportive measures should
be instituted as required.
11
DESCRIPTION
PRAVACHOL (pravastatin sodium) is one of a class of lipid-lowering compounds, the statins,
which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA
reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
conversion of HMG-CoA to mevalonate.
Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a
hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium
salt,
[1S
[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.
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Structural formula: structural formula
Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively
polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It
is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically
insoluble in acetone, acetonitrile, chloroform, and ether.
PRAVACHOL is available for oral administration as 20 mg, 40 mg, and 80 mg tablets. Inactive
ingredients include: croscarmellose sodium, lactose, magnesium oxide, magnesium stearate,
microcrystalline cellulose, and povidone. The 20 mg and 80 mg tablets also contain Yellow
Ferric Oxide and the 40 mg tablet also contains Green Lake Blend (mixture of D&C Yellow No.
10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces
VLDL and TG and increases HDL-C.
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12.3
Pharmacokinetics
General
Absorption: PRAVACHOL is administered orally in the active form. In studies in man, peak
plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on
urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and
absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or
1 hour prior to meals.
Pravastatin plasma concentrations, including area under the concentration-time curve (AUC),
Cmax , and steady-state minimum (Cmin ), are directly proportional to administered dose. Systemic
bioavailability of pravastatin administered following a bedtime dose was decreased 60%
compared to that following an AM dose. Despite this decrease in systemic bioavailability, the
efficacy of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose.
The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted
state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.
Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin
accumulation following once or twice daily administration of PRAVACHOL tablets.
Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.
Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to
6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring
hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40
the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes
extensive first-pass extraction in the liver (extraction ratio 0.66).
Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the
feces. After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes
(i.e., biliary excretion and biotransformation).
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Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for
pravastatin is 1.8 hours in humans.
Specific Populations
Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients
with varying degrees of renal impairment (as determined by creatinine clearance). No effect was
observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite
(SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal
impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour
shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).
Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy
confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for
cirrhotic patients compared to 6-fold for healthy subjects. [See Warnings and Precautions (5.2).]
Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin
was approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65-75 years old) compared with younger men (19-31
years old). In a similar study conducted in women, the mean AUC for pravastatin was
approximately 46% higher and the mean CUE approximately 18% lower in elderly women
(65-78 years old) compared with younger women (18-38 years old). In both studies, Cmax , Tmax ,
and t½ values were similar in older and younger subjects. [See Use in Specific Populations
(8.5).]
Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric
means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years,
N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for C max
were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No
conclusion can be made based on these findings due to the small number of samples and large
variability. [See Use in Specific Populations (8.4).]
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Drug-Drug Interactions
Table 3:
Effect of Coadministered Drugs on the Pharmacokinetics of
Pravastatin
Coadministered Drug and Dosing
Regimen
Pravastatin
Dose (mg)
Change in AUC
Change in C max
Cyclosporine 5 mg/kg single dose
40 mg single dose
↑282%
↑327%
Clarithromycin 500 mg BID for 9 days
40 mg OD for 8 days
↑110%
↑128%
Boceprevir 800 mg TID for 6 days
40 mg single dose
↑63%
↑49%
Darunavir 600 mg BID/Ritonavir 100 mg
BID for 7 days
40 mg single dose
↑81%
↑63%
Colestipol 10 g single dose
20 mg single dose
↓47%
↓53%
Cholestyramine 4 g single dose
Administered simultaneously
Administered 1 hour prior to
cholestyramine
Administered 4 hours after
cholestyramine
20 mg single dose
↓40%
↑12%
↓12%
↓39%
↑30%
↓6.8%
Cholestyramine 24 g OD for 4 weeks
20 mg BID for 8 weeks
5 mg BID for 8 weeks
10 mg BID for 8 weeks
↓51%
↓38%
↓18%
↑4.9%
↑23%
↓33%
Fluconazole
200 mg IV for 6 days
200 mg PO for 6 days
20 mg PO+10 mg IV
20 mg PO+10 mg IV
↓34%
↓16%
↓33%
↓16%
Kaletra 400 mg/100 mg BID for 14 days
20 mg OD for 4 days
↑33%
↑26%
Verapamil IR 120 mg for 1 day and
Verapamil ER 480 mg for 3 days
40 mg single dose
↑31%
↑42%
Cimetidine 300 mg QID for 3 days
20 mg single dose
↑30%
↑9.8%
Antacids 15 mL QID for 3 days
20 mg single dose
↓28%
↓24%
Digoxin 0.2 mg OD for 9 days
20 mg OD for 9 days
↑23%
↑26%
Probucol 500 mg single dose
20 mg single dose
↑14%
↑24%
Warfarin 5 mg OD for 6 days
20 mg BID for 6 days
↓13%
↑6.7%
Itraconazole 200 mg OD for 30 days
40 mg OD for 30 days
↑11% (compared to
Day 1)
↑17% (compared
to Day 1)
Gemfibrozil 600 mg single dose
20 mg single dose
↓7.0%
↓20%
Aspirin 324 mg single dose
20 mg single dose
↑4.7%
↑8.9%
Niacin 1 g single dose
20 mg single dose
↓3.6%
↓8.2%
Diltiazem
20 mg single dose
↑2.7%
↑30%
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Table 3:
Effect of Coadministered Drugs on the Pharmacokinetics of
Pravastatin
Coadministered Drug and Dosing
Regimen
Pravastatin
Dose (mg)
Change in AUC
Change in C max
Grapefruit juice
40 mg single dose
↓1.8%
↑3.7%
BID = twice daily; OD = once daily; QID = four times daily
Table 4:
Effect of Pravastatin on the Pharmacokinetics of Coadministered
Drugs
Pravastatin Dosing
Regimen
Name and Dose
Change in AUC
Change in C max
20 mg BID for 6 days
Warfarin 5 mg OD for 6 days
Change in mean prothrombin time
↑17%
↑0.4 sec
↑15%
20 mg OD for 9 days
Digoxin 0.2 mg OD for 9 days
↑4.6%
↑5.3%
20 mg BID for 4 weeks
10 mg BID for 4 weeks
5 mg BID for 4 weeks
Antipyrine 1.2 g single dose
↑3.0%
↑1.6%
↑ Less than 1%
Not Reported
20 mg OD for 4 days
Kaletra 400 mg/100 mg BID for
14 days
No change
No change
BID = twice daily; OD = once daily
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was
an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These
effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on
body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.
In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and
500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013).
These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times
(500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up
to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on
AUC), there were no drug-induced tumors.
Reference ID: 3954762
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No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella
typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma
cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using
Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a
dominant lethal test in mice or a micronucleus test in mice.
In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any
adverse effects on fertility or general reproductive performance.
13.2
Animal Toxicology and/or Pharmacology
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear
cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of
25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of
80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other
drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion
starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher
than the mean drug level in humans taking the highest recommended dose (as measured by total
enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at
180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the
60 mg/kg/day dose.
When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5-45 mg/kg/day), no
drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-
weight gain was observed during the dosing and 52-day recovery periods as well as slight
thinning of the corpus callosum at the end of the recovery period. This finding was not evident in
rats examined at the completion of the dosing period and was not associated with any
inflammatory or degenerative changes in the brain. The biological relevance of the corpus
callosum finding is uncertain due to the absence of any other microscopic changes in the brain or
peripheral nervous tissue and because it occurred at the end of the recovery period.
Reference ID: 3954762
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Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-
maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day
during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are
approximately ≥1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus
callosum was observed in rats dosed with pravastatin (≥250 mg/kg/day) beginning PND 35 for 3
months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately
equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the
40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.
14
CLINICAL STUDIES
14.1
Prevention of Coronary Heart Disease
In the Pravastatin Primary Prevention Study (WOS),3 the effect of PRAVACHOL on fatal and
nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with
LDL-C levels between 156 to 254 mg/dL (4-6.7 mmol/L). In this randomized, double-blind,
placebo-controlled study, patients were treated with standard care, including dietary advice, and
either PRAVACHOL 40 mg daily (N=3302) or placebo (N=3293) and followed for a median
duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6
months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7),
−27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.
PRAVACHOL significantly reduced the rate of first coronary events (either CHD death or
nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus
174 events in the PRAVACHOL group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure
below]). The risk reduction with PRAVACHOL was similar and significant throughout the entire
range of baseline LDL cholesterol levels. This reduction was also similar and significant across
the age range studied with a 40% risk reduction for patients younger than 55 years and a 27%
risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included
only men, and therefore it is not clear to what extent these data can be extrapolated to a similar
population of female patients.
Reference ID: 3954762
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graph
PRAVACHOL also significantly decreased the risk for undergoing myocardial revascularization
procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary
angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31%
(128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and
there was no increase in death from non-cardiovascular causes.
14.2
Secondary Prevention of Cardiovascular Events
In the LIPID4 study, the effect of PRAVACHOL, 40 mg daily, was assessed in 9014 patients
(7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had
experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris
(3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind,
placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at
randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46
and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and
HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving
aspirin and 76% were receiving antihypertensive medication. Treatment with PRAVACHOL
significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The
risk reduction due to treatment with PRAVACHOL on CHD mortality was consistent regardless
of age. PRAVACHOL significantly reduced the risk for total mortality (by reducing CHD death)
and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of
either MI or hospitalization for unstable angina pectoris.
Reference ID: 3954762
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Table 5:
LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=4512)
Placebo
(N=4502)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality
287 (6.4)
373 (8.3)
24%
0.0004
Secondary Endpoints
Total mortality
498 (11.0)
633 (14.1)
23%
<0.0001
CHD mortality or nonfatal MI
557 (12.3)
715 (15.9)
24%
<0.0001
Myocardial revascularization
procedures (CABG or PTCA)
584 (12.9)
706 (15.7)
20%
<0.0001
Stroke
All-cause
169 (3.7)
204 (4.5)
19%
0.0477
Non-hemorrhagic
154 (3.4)
196 (4.4)
23%
0.0154
Cardiovascular mortality
331 (7.3)
433 (9.6)
25%
<0.0001
In the CARE5 study, the effect of PRAVACHOL, 40 mg daily, on CHD death and nonfatal MI
was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the
preceding 3 to 20 months and who had normal (below the 75th percentile of the general
population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled
study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL.
LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At
baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive
medications. Median (25th, 75th percentile) percent changes from baseline after 6 months
of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4
(−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with
PRAVACHOL significantly reduced the rate of first recurrent coronary events (either CHD
death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and
the risk for stroke or TIA (see Table 6).
Reference ID: 3954762
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Table 6:
CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event
Pravastatin 40 mg
(N=2081)
Placebo
(N=2078)
Risk
Reduction
p-value
Primary Endpoint
CHD mortality or nonfatal MIa
212 (10.2)
274 (13.2)
24%
0.003
Secondary Endpoints
Myocardial revascularization
procedures (CABG or PTCA)
294 (14.1)
391 (18.8)
27%
<0.001
Stroke or TIA
93 (4.5)
124 (6.0)
26%
0.029
a The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.
In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed
by coronary angiography in patients with coronary disease and moderate hypercholesterolemia
(baseline LDL-C range: 130-190 mg/dL). In this double-blind, multicenter, controlled clinical
trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the
difference between pravastatin and placebo for the primary endpoint (per-patient change in mean
coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter
stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum
lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment
group (p=0.02).
In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by
coronary angiography in 885 patients with angina pectoris, angiographically documented
coronary artery disease, and hypercholesterolemia (baseline total cholesterol range:
160-310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were
evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of
coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by
changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
Analysis of pooled events from PLAC I, PLAC II,8 REGRESS, and KAPS9 studies (combined
N=1891) showed that treatment with pravastatin was associated with a statistically significant
reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo
versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to
reduce the rate of nonfatal MI.
Reference ID: 3954762
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14.3
Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)
PRAVACHOL is highly effective in reducing Total-C, LDL-C, and TG in patients with
heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary
hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week,
and the maximum response usually is achieved within 4 weeks. This response is maintained
during extended periods of therapy. In addition, PRAVACHOL is effective in reducing the risk
of acute coronary events in hypercholesterolemic patients with and without previous MI.
A single daily dose is as effective as the same total daily dose given twice a day. In multicenter,
double-blind, placebo-controlled studies of patients with primary hypercholesterolemia,
treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly
decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7).
In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with
primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277)
significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from
baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the
individual studies were consistent with the pooled data (see Table 7).
Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across all
doses produced variable increases in HDL-C (see Table 7).
Table 7:
Primary Hypercholesterolemia Studies: Dose Response of
PRAVACHOL Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From Baseline After 8 Weeksa
Placebo (N=36)
−3%
−4%
+1%
−4%
10 mg (N=18)
−16%
−22%
+7%
−15%
20 mg (N=19)
−24%
−32%
+2%
−11%
40 mg (N=18)
−25%
−34%
+12%
−24%
Mean Percent Changes From Baseline After 6 Weeksb
Placebo (N=162)
0%
−1%
−1%
+1%
80 mg (N=277)
−27%
−37%
+3%
−19%
a A multicenter, double-blind, placebo-controlled study.
b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.
Reference ID: 3954762
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In another clinical trial, patients treated with pravastatin in combination with cholestyramine
(70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or
greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced
increases in TG levels (which are themselves of uncertain clinical significance).
14.4
Hypertriglyceridemia (Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200 mg/dL
and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For
pravastatin-treated subjects, the median (min, max) baseline TG level was 246.0 (200.5,
349.5) mg/dL (see Table 8).
Table 8:
Patients with Fredrickson Type IV Hyperlipidemia Median (25th, 75th
percentile) % Change from Baseline
Pravastatin 40 mg (N=429)
Placebo (N=430)
TG
−21.1 (−34.8, 1.3)
−6.3 (−23.1, 18.3)
Total-C
−22.1 (−27.1, −14.8)
0.2 (−6.9, 6.8)
LDL-C
−31.7 (−39.6, −21.5)
0.7 (−9.0, 10.0)
HDL-C
7.4 (−1.2, 17.7)
2.8 (−5.7, 11.7)
Non-HDL-C
−27.2 (−34.0, −18.5)
−0.8 (−8.2, 7.0)
14.5
Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with genotype
E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 9.
Table 9:
Patients with Fredrickson Type III Dysbetalipoproteinemia Median
(min, max) % Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
Study 1
Total-C
386.5 (245.0, 672.0)
−32.7 (−58.5, 4.6)
TG
443.0 (275.0, 1299.0)
−23.7 (−68.5, 44.7)
VLDL-Ca
206.5 (110.0, 379.0)
−43.8 (−73.1, −14.3)
LDL-Ca
117.5 (80.0, 170.0)
−40.8 (−63.7, 4.6)
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Table 9:
Patients with Fredrickson Type III Dysbetalipoproteinemia Median
(min, max) % Change from Baseline
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=20)
HDL-C
30.0 (18.0, 88.0)
6.4 (−45.0, 105.6)
Non-HDL-C
344.5 (215.0, 646.0)
−36.7 (−66.3, 5.8)
a N=14
Median (min, max)
at Baseline (mg/dL)
Median % Change (min, max)
Pravastatin 40 mg (N=26)
Study 2
Total-C
340.3 (230.1, 448.6)
−31.4 (−54.5, −13.0)
TG
343.2 (212.6, 845.9)
−11.9 (−56.5, 44.8)
VLDL-C
145.0 (71.5, 309.4)
−35.7 (−74.7, 19.1)
LDL-C
128.6 (63.8, 177.9)
−30.3 (−52.2, 13.5)
HDL-C
38.7 (27.1, 58.0)
5.0 (−17.7, 66.7)
Non-HDL-C
295.8 (195.3, 421.5)
−35.5 (−81.0, −13.5)
14.6
Pediatric Clinical Study
A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with
heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2
years. The children (aged 8-13 years) were randomized to placebo (N=63) or 20 mg of
pravastatin daily (N=65) and the adolescents (aged 14-18 years) were randomized to placebo
(N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level
>95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of
familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL
in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL) groups,
respectively.
Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children
and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was
similar.
Reference ID: 3954762
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Table 10:
Lipid-Lowering Effects of Pravastatin in Pediatric Patients with
Heterozygous Familial Hypercholesterolemia: Least-Squares Mean %
Change from Baseline at Month 24 (Last Observation Carried
Forward: Intent-to-Treat)a
Pravastatin
20 mg
(Aged 8-13
years)
N=65
Pravastatin
40 mg
(Aged 14-18
years)
N=41
Combined
Pravastatin
(Aged 8-18
years)
N=106
Combined
Placebo
(Aged 8-18
years)
N=108
95% CI of the
Difference Between
Combined
Pravastatin and
Placebo
LDL-C
−26.04b
−21.07b
−24.07b
−1.52
(−26.74, −18.86)
TC
−20.75b
−13.08b
−17.72b
−0.65
(−20.40, −13.83)
HDL-C
1.04
13.71
5.97
3.13
(−1.71, 7.43)
TG
−9.58
−0.30
−5.88
−3.27
(−13.95, 10.01)
ApoB
(N)
−23.16b
(61)
−18.08b
(39)
−21.11b
(100)
−0.97
(106)
(−24.29, −16.18)
a The above least-squares mean values were calculated based on log-transformed lipid values.
b Significant at p≤0.0001 when compared with placebo.
The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin group
compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.
The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children.
The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
15
REFERENCES
1. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to
mechanisms and disorders. N Engl J Med. 1967;276: 34-44, 94-103, 148-156, 215-225,
273-281.
2. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of
lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol. 1996;10(6):439-446.
3. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study
Group (WOS). Prevention of coronary heart disease with pravastatin in men with
hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
Reference ID: 3954762
33
4. The Long-term Intervention with Pravastatin in Ischemic Disease Group (LIPID). Prevention
of cardiovascular events and death with pravastatin in patients with coronary heart disease
and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
5. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial
Investigators (CARE). The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
6. Pitt B, Mancini GBJ, Ellis SG, et al, for the PLAC I Investigators. Pravastatin limitation of
atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression
and clinical events. J Am Coll Cardiol. 1995;26:1133-1139.
7. Jukema JW, Bruschke AVG, van Boven AJ, et al, for the Regression Growth Evaluation
Statin Study Group (REGRESS). Effects of lipid lowering by pravastatin on progression and
regression of coronary artery disease in symptomatic man with normal to moderately
elevated serum cholesterol levels. Circ. 1995;91:2528-2540.
8. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the
carotid arteries: Design features of a clinical trial with carotid atherosclerosis outcome
(PLAC II). Control Clin Trials. 1992;13:495-506.
9. Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study
(KAPS). A population-based primary preventive trial of the effect of LDL lowering on
atherosclerotic progression in carotid and femoral arteries. Circ. 1995;92:1758-1764.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
PRAVACHOL (pravastatin sodium) Tablets are supplied as:
20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 20” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5178-05). Bottles contain a desiccant canister.
40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a “P” embossed on one side
and “PRAVACHOL 40” engraved on the opposite side. They are supplied in bottles of 90
(NDC 0003-5194-10). Bottles contain a desiccant canister.
Reference ID: 3954762
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80 mg tablets: Yellow, oval-shaped tablet with “BMS” on one side and “80” on the other side.
They are supplied in bottles of 90 (NDC 0003-5195-10). Bottles contain a desiccant canister.
16.2
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.
17
PATIENT COUNSELING INFORMATION
Muscle Pain
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after
discontinuing PRAVACHOL [see Warnings and Precautions (5.1)].
Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of PRAVACHOL,
and thereafter when clinically indicated. All patients treated with PRAVACHOL should be
advised to promptly report any symptoms that may indicate liver injury, including fatigue,
anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and
Precautions (5.2)].
Embryofetal Toxicity
Advise females of reproductive potential of the risk to a fetus, to use effective contraception
during treatment, and to inform their healthcare provider of a known or suspected pregnancy [see
Contraindications (4.3), Use in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment with PRAVACHOL [see Contraindications
(4.4), Use in Specific Populations (8.2)].
Reference ID: 3954762
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Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Product of Japan
[Print Code]
Revised [July 2016]
Reference ID: 3954762
36
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custom-source
|
2025-02-12T13:46:16.111321
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019898s066lbl.pdf', 'application_number': 19898, 'submission_type': 'SUPPL ', 'submission_number': 66}
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11,831
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALTACE safely and effectively. See full prescribing information for
ALTACE.
ALTACE (ramipril) Capsules, Oral
Initial U.S. Approval: 1991
WARNING: AVOID USE IN PREGNANCY
See full prescribing information for complete boxed warning
•
When used in pregnancy, ACE inhibitors can cause injury and
death to the developing fetus. When pregnancy is detected,
discontinue ALTACE® as soon as possible (5.6).
----------------------------RECENT MAJOR CHANGES-------------------------
WARNINGS AND PRECAUTIONS
•
Dual Blockade of the Renin-Angiotensin-Aldosterone System:
Telmisartan (5.7) 10/2010
----------------------------INDICATIONS AND USAGE--------------------------
•
ALTACE® is indicated for the treatment of hypertension. It may be used
alone or in combination with thiazide diuretics. (1.1).
•
In patients 55 years or older at high risk of developing a major
cardiovascular event, ALTACE is indicated to reduce the risk of
myocardial infarction, stroke, or death from cardiovascular causes (1.2).
•
ALTACE is indicated in stable patients who have demonstrated clinical
signs of congestive heart failure post-myocardial infarction (1.3).
----------------------DOSAGE AND ADMINISTRATION----------------------
•
Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage
according to blood pressure response after 2–4 weeks of treatment. The
usual maintenance dose following titration is 2.5 mg to 20 mg daily as a
single dose or equally divided doses (2.1).
•
Reduction in the risk of myocardial infarction, stroke, or death from
cardiovascular causes: 2.5 mg once daily for 1 week, 5 mg once daily for
3 weeks, and increased as tolerated to a maintenance dose of 10 mg once
daily (2.2).
•
Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice
daily. If patient becomes hypotensive at this dose, decrease dosage to
1.25 mg twice daily. Increase dose as tolerated toward a target dose of
5 mg twice daily, with dosage increases about 3 weeks apart (2.3).
•
Dosage adjustment: See respective sections pertaining to dosage
adjustment in special situations (2.5).
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg (3)
-------------------------------CONTRAINDICATIONS-----------------------------
Angioedema related to previous treatment with an ACE inhibitor, or a history
of hereditary or idiopathic angioedema. (4).
-----------------------WARNINGS AND PRECAUTIONS-----------------------
ACE inhibitor use has been associated with the following:
•
Angioedema, with increased risk in patients with a prior history (5.1)
•
Hypotension and hyperkalemia (5.5, 5.8)
•
Renal impairment: monitor renal function during therapy (5.3)
•
Increased risk of renal impairment when combined with another blocker
of the rein-angiotensin-aldosterone system (5.7)
•
Rare cholestatic jaundice and hepatic failure (5.2)
•
Rare neutropenia and agranulocytosis (5.4)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in patients with hypertension included
headache, dizziness, fatigue, and cough (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact King
Pharmaceuticals, Inc. at 1-800-546-4905 or DSP@kingpharm.com or the
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
•
Diuretics: Possibility of excessive hypotension (7.1).
•
Lithium: Use with caution (7.3).
•
Gold: Nitritoid reactions have been reported (7.4).
•
NSAIDS use may lead to increased risk of renal impairment and loss of
antihypertensive effect (7.5).
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Pregnancy: Discontinue drug if pregnancy is detected (5.6, 8.1).
•
Nursing mothers: ALTACE use is not recommended in nursing mothers
(8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 06/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: USE IN PREGNANCY
1 INDICATIONS AND USAGE
1.1 Hypertension
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death
from Cardiovascular Causes
1.3 Heart Failure Post-Myocardial Infarction
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
2.3 Heart Failure Post-Myocardial Infarction
2.4 General Dosing Information
2.5 Dosage Adjustment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hepatic Failure and Impaired Liver Function
5.3 Renal Impairment
5.4 Neutropenia and Agranulocytosis
5.5 Hypotension
5.6 Fetal/Neonatal Morbidity and Mortality
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
5.8 Hyperkalemia
5.9 Cough
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
6.3 Clinical Laboratory Test Findings
7 DRUG INTERACTIONS
7.1 Diuretics
7.2 Other Antihypertensive Agents
7.3 Lithium
7.4 Gold
7.5 Non-Steroidal Anti-Inflammatory Agents including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
7.6 Other
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Hypertension
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
14.3 Heart Failure Post-Myocardial Infarction
FULL PRESCRIBING INFORMATION
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
17.2 Neutropenia
17.3 Symptomatic Hypotension
17.4 Pregnancy
17.5 Hyperkalemia
LabelGraphics1
LabelGraphics2
LabelGraphics3
LabelGraphics4
*Sections or subsections omitted from the full prescribing information are not listed
WARNING: USE IN PREGNANCY
•
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause
injury and even death to the developing fetus. When pregnancy is detected, discontinue
ALTACE® as soon as possible (5.6).
1 INDICATIONS AND USAGE
1.1 Hypertension
ALTACE® is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
ALTACE is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a
history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other
cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or
documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes.
ALTACE can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering
therapy) [see CLINICAL STUDIES (14.2)].
1.3 Heart Failure Post-Myocardial Infarction
ALTACE is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first
few days after sustaining acute myocardial infarction. Administration of ALTACE to such patients has been shown to
decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and
progression to severe/resistant heart failure [see CLINICAL STUDIES (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood
pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two
equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the
dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not
controlled with ALTACE alone, a diuretic can be added.
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a
maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, ALTACE can
also be given as a divided dose.
2.3 Heart Failure Post-Myocardial Infarction
For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the
recommended starting dose of ALTACE is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this
dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a
target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood
pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may
diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not
preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see
WARNINGS AND PRECAUTIONS (5.5), DRUG INTERACTIONS (7.1)].
2.4 General Dosing Information
Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a
small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is
not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and
stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing
diuretics can lead to increases of serum potassium [see WARNINGS AND PRECAUTIONS (5.8)].
2.5 Dosage Adjustment
Renal Impairment
Establish baseline renal function in patients initiating ALTACE. Usual regimens of therapy with ALTACE may be
followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25%
of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see USE IN SPECIFIC
POPULATIONS (8.6)].
Hypertension
For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily.
Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction
For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily. The
dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical
response and tolerability.
Volume Depletion or Renal Artery Stenosis
Blood pressure decreases associated with any dose of ALTACE depend, in part, on the presence or absence of volume
depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are
suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.
3 DOSAGE FORMS AND STRENGTHS
ALTACE (ramipril) is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.
4 CONTRAINDICATIONS
ALTACE is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient
who has experienced angioedema during therapy with any other ACE inhibitor).
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the
metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including
ALTACE) may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while
receiving an ACE inhibitor.
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE
inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, discontinue treatment with ALTACE and institute appropriate therapy immediately. Where there
is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g.,
subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [see ADVERSE REACTIONS (6)].
In considering the use of ALTACE, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema
in Black patients than in non-Black patients.
In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was
reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different
statistically.
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal
pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase
levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-
threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were
temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly
with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein
apheresis with dextran sulfate absorption.
5.2 Hepatic Failure and Impaired Liver Function
Rarely, ACE inhibitors, including ALTACE, have been associated with a syndrome that starts with cholestatic jaundice
and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood.
Discontinue ALTACE if patient develops jaundice or marked elevations of hepatic enzymes.
As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver
function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried
out in hypertensive patients with impaired liver function.
5.3 Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in
susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity
of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ALTACE, may be associated with
oliguria or progressive azotemia and rarely with acute renal failure or death.
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum
creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon
discontinuation of ALTACE and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of
therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in
blood urea nitrogen and serum creatinine, usually minor and transient, especially when ALTACE has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage
reduction of ALTACE and/or discontinuation of the diuretic may be required.
5.4 Neutropenia and Agranulocytosis
In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and
hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow
depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-
vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white
blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal
function.
5.5 Hypotension
General Considerations
ALTACE can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been
increased. Like other ACE inhibitors, ALTACE, has been only rarely associated with hypotension in uncomplicated
hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-
depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume-
and salt-depletion before initiating therapy with ALTACE.
If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of
physiological saline. ALTACE treatment usually can be continued following restoration of blood pressure and volume.
Heart Failure Post-Myocardial Infarction
In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of ALTACE. If the initial dose of 2.5 mg ALTACE cannot
be tolerated, use an initial dose of 1.25 mg ALTACE to avoid excessive hypotension. Consider reducing the dose of
concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause
excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.
In such patients, initiate ALTACE therapy under close medical supervision and follow patients closely for the first 2
weeks of treatment and whenever the dose of ALTACE or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin
II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of
this mechanism can be corrected by volume expansion.
5.6 Fetal/Neonatal Morbidity and Mortality
Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to
pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, discontinue
ACE inhibitors as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal
injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.
Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in
this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were caused by the ACE inhibitor exposure.
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first
trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants
whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is
small and the findings of this study have not yet been confirmed.
Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin
aldosterone system will be found. In these rare cases, inform mothers about the potential hazards to their fetuses, and
perform serial ultrasound examinations to assess the intraamniotic environment.
If oligohydramnios is observed, discontinue ALTACE unless it is considered life-saving for the mother. Contraction stress
testing, a nonstress test, or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible
injury.
Closely observe infants with histories of in utero exposure to ACE inhibitors for hypotension, oliguria, and hyperkalemia.
If oliguria occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusion or dialysis
may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which
crosses the placenta, can be removed from the neonatal circulation by these means, but limited experience has not shown
that such removal is central to the treatment of these infants.
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Telmisartan
The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ
damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56
months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite
endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced
an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis)
compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not
recommended.
5.8 Hyperkalemia
In clinical trials with ALTACE, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of
hypertensive patients receiving ALTACE. In most cases, these were isolated values, which resolved despite continued
therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing
diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all,
with ALTACE [ see DRUG INTERACTIONS (7.1)].
5.9 Cough
Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been
reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin
converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Hypertension
ALTACE has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in
U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at
Reference ID: 3004966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
least one year. The overall incidence of reported adverse events was similar in ALTACE and placebo patients. The most
frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ALTACE in
placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one
was more common in ALTACE patients than in patients given placebo. Generally the side effects were mild and transient,
and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side
effect was required in approximately 3% of U.S. patients treated with ALTACE. The most common reasons for
discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).
Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled
trials in more than 1% of patients treated with ALTACE, only asthenia (fatigue) was more common on ALTACE than
placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).
In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ALTACE
group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE
inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased
cough was seen in almost 12% of ALTACE patients, with about 4% of patients requiring discontinuation of treatment.
Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
HOPE Study
Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or
temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril
Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials [see WARNINGS AND
PRECAUTIONS (5.1)].
Table 1. Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study
Placebo
(N=4652)
ALTACE
(N=4645)
Discontinuation at any time
32%
34%
Permanent discontinuation
28%
29%
Reasons for stopping
Cough
2%
7%
Hypotension or dizziness
1.5%
1.9%
Angioedema
0.1%
0.3%
Heart Failure Post-Myocardial Infarction
AIRE Study
Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in
more than 1% of patients and more frequently on ALTACE are shown below. The incidences are from the AIRE study.
The follow-up time was between 6 and 46 months for this study.
Table 2. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-
Controlled (AIRE) Mortality Study
Adverse Event
Placebo
(N=982)
ALTACE
(N=1004)
Hypotension
5%
11%
Cough increased
4%
8%
Dizziness
3%
4%
Angina pectoris
2%
3%
Nausea
1%
2%
Postural hypotension
1%
2%
Syncope
1%
2%
Vomiting
0.5%
2%
Vertigo
0.7%
2%
Abnormal kidney function
0.5%
1%
Diarrhea
0.4%
1%
Reference ID: 3004966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of ALTACE patients), or rarer events seen in
post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Body as a whole: Anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.1)].
Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see WARNINGS AND
PRECAUTIONS (5.5) ], syncope, and palpitations.
Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.
Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in
0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic.
Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor,
usually transient, increases in blood urea nitrogen and serum creatinine when taking ALTACE, particularly when
ALTACE was given concomitantly with a diuretic [see WARNINGS AND PRECAUTIONS (5.3)].
Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ALTACE [see
WARNINGS AND PRECAUTIONS (5.1) ].
Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes
suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased
salivation, and taste disturbance.
Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever),
photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and
Stevens-Johnson syndrome.
Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia,
neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA,
an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity,
rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has
been reported.
Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.
6.2 Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during
ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal
relationship is unknown.
6.3 Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE
alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5%
of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases
required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal
insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to
be especially likely in patients with renal artery stenosis [see WARNINGS AND PRECAUTIONS (5.3)]. As ramipril
decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium
sparing diuretics with caution, and monitor the patient’s serum potassium frequently [see WARNINGS AND
PRECAUTIONS (5.8)].
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%,
respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving
ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated
with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been
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reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials,
less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or
abnormal liver-function tests.
7 DRUG INTERACTIONS
7.1 Diuretics
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an
excessive reduction of blood pressure after initiation of therapy with ALTACE. The possibility of hypotensive effects
with ALTACE can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to
initiation of treatment with ALTACE. If this is not possible, reduce the starting dose [see DOSAGE AND
ADMINISTRATION (2)].
ALTACE can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if
concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
7.2 Other Antihypertensive Agents
Limited experience in controlled and uncontrolled trials combining ALTACE with a calcium channel blocker, a loop
diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE
inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower
blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart
rate).
In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased
incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups
receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual
Blockade of the Renin-Angiotensin-Aldosterone System (5.7)].
7.3 Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors
during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also
used, the risk of lithium toxicity may be increased.
7.4 Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in
patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including
ALTACE.
7.5 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function,
co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result
in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving ramipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
7.6 Other
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Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine,
indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation
effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum
phenprocoumon levels or interfere with the patients’ state of anticoagulation.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters) [see WARNINGS AND PRECAUTIONS
(5.6)].
8.3 Nursing Mothers
Ingestion of a single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in
breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single
dose, do not use ALTACE in nursing mothers.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in
very young rats given a single dose of ALTACE.
8.5 Geriatric Use
Of the total number of patients who received ALTACE in U.S. clinical studies of ALTACE, 11.0% were ≥65 years of age
while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients
and younger patients, and other reported clinical experience has not identified differences in responses between the elderly
and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under
the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
8.6 Renal Impairment
A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment
who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of
creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and
severe impairment (<15 mL/min). On average, the AUC0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold
higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the
group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted
downward in patients with moderate-to-severe renal impairment.
10 OVERDOSAGE
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as
high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most
likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might
accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be
effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but
angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril
is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of
normal saline solution.
11 DESCRIPTION
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Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar
organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3
phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell
contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell
contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is: structural formula
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by
hepatic cleavage of the ester group.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl
dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II
also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II,
which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up
to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from
baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline
greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide
for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and
approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see WARNINGS
AND PRECAUTIONS (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity.
The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE
activity, thereby reducing angiotensin II formation in tissue and plasma.
Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated.
While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the renin-
angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension.
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Although ALTACE was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin
hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than
non-Black patients.
12.2 Pharmacodynamics
Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after
dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause
plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining
24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE
binding sites by ramiprilat and relatively slow release from those sites.
12.3 Pharmacokinetics
Absorption
Following oral administration of ALTACE, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The
extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal
tract, although the rate of absorption is reduced.
In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved
in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the
concomitant liquid or food.
Distribution
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak
plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is
about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of
0.01 µg/mL–10 µg/mL.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril,
and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which
are inactive.
Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The
24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg-20 mg dose range. The absolute
bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared
with the same dose of ramipril given intravenously.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state
concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses
(2.5 mg), but the difference is clinically insignificant.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase,
terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral
compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent
binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent
elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal
elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the
ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ALTACE
5 mg-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and
trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these
patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of
diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak
concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic
function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
Excretion
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After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and
about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or
unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the
administered dose is recovered in urine as unchanged ramipril.
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function.
Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough
ramiprilat levels and slightly longer times to peak concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of
up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are
about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No
mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in
a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and
degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as
500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body
surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the
recommended human dose.
14 CLINICAL STUDIES
14.1 Hypertension
ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for
hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and
standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is
infrequent, although it can occur in patients who are salt- and/or volume-depleted [see WARNINGS AND
PRECAUTIONS (5.5)]. Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect
greater than that seen with either agent alone.
In single-dose studies, doses of 5 mg–20 mg of ALTACE lowered blood pressure within 1–2 hours, with peak reductions
achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12
weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing
systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of
peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titration study comparing
divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive
effect with once-daily dosing is not adequately maintained.
In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements.
The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt
withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other
ACE inhibitors, beta-blockers, and thiazide diuretics. ALTACE was approximately as effective as other ACE inhibitors
and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than
ramipril.
ALTACE was less effective in blacks than in Caucasians. The effectiveness of ALTACE was not influenced by age, sex,
or weight.
In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied
by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
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The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial design study
conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a
major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes
that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low
HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment
with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low
ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg
orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction,
stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3
components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to
the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of
treatment.
Table 3. Summary of Combined Components and Endpoints—HOPE Study
Outcome
Placebo
(N=4652)
n (%)
ALTACE
(N=4645)
n (%)
Relative Risk
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
826 (17.8%)
651 (14.0%)
0.78 (0.70–0.86)
P=0.0001
Component
Endpoint
Death from
cardiovascular causes
377 (8.1%)
282 (6.1%)
0.74 (0.64–0.87)
P=0.0002
Myocardial infarction
570 (12.3%)
459 (9.9%)
0.80 (0.70–0.90)
P=0.0003
Stroke
226 (4.9%)
156 (3.4%)
0.68 (0.56–0.84)
P=0.0002
Overall Mortality
Death from any cause
569 (12.2%)
482 (10.4%)
0.84 (0.75–0.95)
P=0.005
Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from
Cardiovascular Causes in the Ramipril Group and the Placebo Group
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graph
ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease
(e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient
data to determine whether or not ALTACE was equally effective in ethnic subgroups.
This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor.
Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to those in the
overall study population.
Table 4. Summary of Combined Endpoints and Components in Diabetics—HOPE Study
Outcome
Placebo
(N=1769)
n (%)
ALTACE
(N=1808)
n (%)
Relative Risk
Reduction
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
351 (19.8%)
277 (15.3%)
0.25 (0.12–0.36)
P=0.0004
Component
Endpoint
Death from
cardiovascular causes
172 (9.7%)
112 (6.2%)
0.37 (0.21–0.51)
P=0.0001
Myocardial infarction
229 (12.9%)
185 (10.2%)
0.22 (0.06–0.36)
P=0.01
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Stroke
108 (6.1%)
76 (4.2%)
0.33 (0.10–0.50)
P=0.007
Figure 2. The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction,
Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups graph
Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the
number of patients in each group. The dashed line indicates overall relative risk.
The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, beta-
blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
14.3 Heart Failure Post-Myocardial Infarction
ALTACE was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-
blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2–9 days after an acute
myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction.
Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or
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valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had
received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of
treatment was 5 days.
Patients randomized to ALTACE treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused
undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a
target regimen (achieved in 77% of patients randomized to ALTACE) of 5 mg twice daily. Patients were then followed
for an average of 15 months, with the range of follow-up between 6 and 46 months.
The use of ALTACE was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of
the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of
congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively.
The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the
initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in
patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80%
of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers
(about 15%), and digoxin (about 12%).
16 HOW SUPPLIED/STORAGE AND HANDLING
ALTACE is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules. Descriptions of ALTACE capsules are
summarized below.
Capsule Strength
Capsule Color
Package
Configuration
NDC#
1.25 mg
yellow
Bottle of 100
61570-110-01
2.5 mg
orange
Bottle of 100
61570-111-01
5 mg
red
Bottle of 100
61570-112-01
10 mg
Process Blue
Bottle of 100
61570-120-01
Dispense in well-closed container with safety closure.
Store at controlled room temperature (59º–86ºF).
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the
first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes,
lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing
physician.
17.2 Neutropenia
Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of
neutropenia.
17.3 Symptomatic Hypotension
Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported.
Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can
lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
17.4 Pregnancy
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Inform female patients of childbearing age about the consequences of exposure to ACE inhibitors during pregnancy.
Advise these patients to report pregnancies to their physicians as soon as possible.
17.5 Hyperkalemia
Advise patients not to use salt substitutes containing potassium without consulting their physician.
Rx Only
Prescribing Information as of June 2011
Distributed by:
Monarch Pharmaceuticals, Inc.
Bristol, TN 37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Manufactured by:
King Pharmaceuticals, Inc.
Bristol, TN 37620
Label Code #60793
This label may not be the latest approved by FDA.
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custom-source
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2025-02-12T13:46:16.216791
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALTACE safely and effectively. See full prescribing information for
ALTACE.
ALTACE (ramipril) Capsules, Oral
Initial U.S. Approval: 1991
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning
When pregnancy is detected, discontinue ALTACE as soon
as possible (5.6).
Drugs that act directly on the renin-angiotensin system can
cause injury and death to the developing fetus (5.6).
----------------------------RECENT MAJOR CHANGES--------------------------
Contraindications
10/2013
Warnings and Precautions, Anaphylactoid and Possibly Related Reactions
(5.1)
9/2013
Warnings and Precautions, Dual Blockade of the Renin-Angiotensin-
Aldosterone System (5.7)
10/2013
----------------------------INDICATIONS AND USAGE--------------------------
ALTACE® is indicated for the treatment of hypertension. It may be used alone
or in combination with thiazide diuretics. (1.1).
In patients 55 years or older at high risk of developing a major cardiovascular
event, ALTACE is indicated to reduce the risk of myocardial infarction,
stroke, or death from cardiovascular causes (1.2).
ALTACE is indicated in stable patients who have demonstrated clinical signs
of congestive heart failure post-myocardial infarction (1.3).
----------------------DOSAGE AND ADMINISTRATION----------------------
Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage
according to blood pressure response after 2–4 weeks of treatment. The usual
maintenance dose following titration is 2.5 mg to 20 mg daily as a single dose
or equally divided doses (2.1).
Reduction in the risk of myocardial infarction, stroke, or death from
cardiovascular causes: 2.5 mg once daily for 1 week, 5 mg once daily for 3
weeks, and increased as tolerated to a maintenance dose of 10 mg once daily
(2.2).
Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice daily.
If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg twice
daily. Increase dose as tolerated toward a target dose of 5 mg twice daily, with
dosage increases about 3 weeks apart (2.3).
Dosage adjustment: See respective sections pertaining to dosage adjustment in
special situations (2.5).
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
Angioedema related to previous treatment with an ACE inhibitor, or a history
of hereditary or idiopathic angioedema. (4).
Do not co-administer aliskiren with ALTACE in patients with diabetes. (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
ACE inhibitor use has been associated with the following:
Angioedema, with increased risk in patients with a prior history or when
combined with mTOR inhibitors (5.1)
Hypotension and hyperkalemia (5.5, 5.8)
Renal impairment: monitor renal function during therapy. (5.3)
Increased risk of renal impairment when combined with another blocker of the
rein-angiotensin-aldosterone system; Avoid concomitant use with aliskiren in
patients with moderate to severe renal impairment. (5.7)
Rare cholestatic jaundice and hepatic failure (5.2)
Rare neutropenia and agranulocytosis (5.4)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in patients with hypertension included
headache, dizziness, fatigue, and cough (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at
1-800-438-1985 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
Diuretics: Possibility of excessive hypotension (7.1).
Lithium: Use with caution (7.3).
Gold: Nitritoid reactions have been reported (7.4).
NSAIDS use may lead to increased risk of renal impairment and loss of
antihypertensive effect (7.5).
mTOR inhibitor use may increase angioedema risk (7.7)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Discontinue drug if pregnancy is detected (5.6, 8.1).
Nursing mothers: ALTACE use is not recommended in nursing mothers (8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 10/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: FETAL TOXICITY
1 INDICATIONS AND USAGE
1.1 Hypertension
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death
from Cardiovascular Causes
1.3 Heart Failure Post-Myocardial Infarction
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
2.3 Heart Failure Post-Myocardial Infarction
2.4 General Dosing Information
2.5 Dosage Adjustment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hepatic Failure and Impaired Liver Function
5.3 Renal Impairment
5.4 Neutropenia and Agranulocytosis
5.5 Hypotension
5.6 Fetal Toxicity
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
5.8 Hyperkalemia
5.9 Cough
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
6.3 Clinical Laboratory Test Findings
7 DRUG INTERACTIONS
7.1 Diuretics
7.2 Other Antihypertensive Agents
7.3 Lithium
7.4 Gold
7.5 Non-Steroidal Anti-Inflammatory Agents including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
7.6 Aliskiren
7.7 mTOR Inhibitors
7.8 Other
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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_______________________________________________________________________________________________________________________________________
14 CLINICAL STUDIES
17.1 Angioedema
14.1 Hypertension
17.2 Neutropenia
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
17.3 Symptomatic Hypotension
Cardiovascular Causes
17.4 Pregnancy
14.3 Heart Failure Post-Myocardial Infarction
17.5 Hyperkalemia
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed
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FULL PRESCRIBING INFORMATION
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ALTACE as soon as possible (5.6).
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus (5.6).
1 INDICATIONS AND USAGE
1.1 Hypertension
ALTACE® is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
ALTACE is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a
history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other
cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or
documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes.
ALTACE can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering
therapy) [see Clinical Studies (14.2)].
1.3 Heart Failure Post-Myocardial Infarction
ALTACE is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first
few days after sustaining acute myocardial infarction. Administration of ALTACE to such patients has been shown to
decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and
progression to severe/resistant heart failure [see Clinical Studies (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood
pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two
equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the
dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not
controlled with ALTACE alone, a diuretic can be added.
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a
maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, ALTACE can
also be given as a divided dose.
2.3 Heart Failure Post-Myocardial Infarction
For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the
recommended starting dose of ALTACE is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this
dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a
target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood
pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may
diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not
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preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see
Warnings and Precautions (5.5), Drug Interactions (7.1)].
2.4 General Dosing Information
Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a
small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is
not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and
stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing
diuretics can lead to increases of serum potassium [see Warnings and Precautions (5.8)].
2.5 Dosage Adjustment
Renal Impairment
Establish baseline renal function in patients initiating ALTACE. Usual regimens of therapy with ALTACE may be
followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25%
of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific Populations
(8.6)].
Hypertension
For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily.
Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction
For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily. The
dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical
response and tolerability.
Volume Depletion or Renal Artery Stenosis
Blood pressure decreases associated with any dose of ALTACE depend, in part, on the presence or absence of volume
depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are
suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.
3 DOSAGE FORMS AND STRENGTHS
ALTACE (ramipril) is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.
4 CONTRAINDICATIONS
ALTACE is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient
who has experienced angioedema during therapy with any other ACE inhibitor).
Do not co-administer aliskiren with ALTACE in patients with diabetes.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the
metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including
ALTACE) may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while
receiving an ACE inhibitor.
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE
inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
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tongue, or glottis occurs, discontinue treatment with ALTACE and institute appropriate therapy immediately. Where there
is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g.,
subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [see Adverse Reactions (6)].
In considering the use of ALTACE, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema
in Black patients than in non-Black patients.
In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was
reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different
statistically.
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. [see
Drug Interactions (7.7)]
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal
pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase
levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-
threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were
temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly
with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein
apheresis with dextran sulfate absorption.
5.2 Hepatic Failure and Impaired Liver Function
Rarely, ACE inhibitors, including ALTACE, have been associated with a syndrome that starts with cholestatic jaundice
and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood.
Discontinue ALTACE if patient develops jaundice or marked elevations of hepatic enzymes.
As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver
function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried
out in hypertensive patients with impaired liver function.
5.3 Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in
susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity
of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ALTACE, may be associated with
oliguria or progressive azotemia and rarely with acute renal failure or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum
creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon
discontinuation of ALTACE and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of
therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in
blood urea nitrogen and serum creatinine, usually minor and transient, especially when ALTACE has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage
reduction of ALTACE and/or discontinuation of the diuretic may be required.
5.4 Neutropenia and Agranulocytosis
In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and
hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow
depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-
vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white
blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal
function.
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5.5 Hypotension
General Considerations
ALTACE can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been
increased. Like other ACE inhibitors, ALTACE, has been only rarely associated with hypotension in uncomplicated
hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-
depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume-
and salt-depletion before initiating therapy with ALTACE.
If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of
physiological saline. ALTACE treatment usually can be continued following restoration of blood pressure and volume.
Heart Failure Post-Myocardial Infarction
In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of ALTACE. If the initial dose of 2.5 mg ALTACE cannot
be tolerated, use an initial dose of 1.25 mg ALTACE to avoid excessive hypotension. Consider reducing the dose of
concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause
excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.
In such patients, initiate ALTACE therapy under close medical supervision and follow patients closely for the first 2
weeks of treatment and whenever the dose of ALTACE or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin
II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of
this mechanism can be corrected by volume expansion.
5.6 Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal
renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with
fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,
hypotension, renal failure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible [see Use in
Specific Populations (8.1)].
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased
risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to
monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on ALTACE and other agents
that affect the RAS.
Telmisartan
The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ
damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56
months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite
endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced
an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis)
compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not
recommended.
Aliskiren
Do not co-administer aliskiren with ALTACE in patients with diabetes. Avoid concomitant use of aliskiren with
ALTACE in patients with renal impairment (GFR <60 mL/min/1.73 m2) [see Drug Interactions (7.6)].
5.8 Hyperkalemia
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In clinical trials with ALTACE, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of
hypertensive patients receiving ALTACE. In most cases, these were isolated values, which resolved despite continued
therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing
diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all,
with ALTACE [see Drug Interactions (7.1)].
5.9 Cough
Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been
reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin
converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Hypertension
ALTACE has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in
U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at
least one year. The overall incidence of reported adverse events was similar in ALTACE and placebo patients. The most
frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ALTACE in
placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one
was more common in ALTACE patients than in patients given placebo. Generally the side effects were mild and transient,
and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side
effect was required in approximately 3% of U.S. patients treated with ALTACE. The most common reasons for
discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).
Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled
trials in more than 1% of patients treated with ALTACE, only asthenia (fatigue) was more common on ALTACE than
placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).
In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ALTACE
group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE
inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased
cough was seen in almost 12% of ALTACE patients, with about 4% of patients requiring discontinuation of treatment.
Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
HOPE Study
Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or
temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril
Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials [see Warnings and Precautions
(5.1)].
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Table 1. Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study
Placebo
(N=4652)
ALTACE
(N=4645)
Discontinuation at any time
32%
34%
Permanent discontinuation
28%
29%
Reasons for stopping
Cough
2%
7%
Hypotension or dizziness
1.5%
1.9%
Angioedema
0.1%
0.3%
Heart Failure Post-Myocardial Infarction
AIRE Study
Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in
more than 1% of patients and more frequently on ALTACE are shown below. The incidences are from the AIRE study.
The follow-up time was between 6 and 46 months for this study.
Table 2. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-
Controlled (AIRE) Mortality Study
Adverse Event
Placebo
(N=982)
ALTACE
(N=1004)
Hypotension
5%
11%
Cough increased
4%
8%
Dizziness
3%
4%
Angina pectoris
2%
3%
Nausea
1%
2%
Postural hypotension
1%
2%
Syncope
1%
2%
Vomiting
0.5%
2%
Vertigo
0.7%
2%
Abnormal kidney function
0.5%
1%
Diarrhea
0.4%
1%
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of ALTACE patients), or rarer events seen in
post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Body as a whole: Anaphylactoid reactions [see Warnings and Precautions (5.1)].
Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see Warnings and Precautions
(5.5)], syncope, and palpitations.
Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.
Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in
0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic.
Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor,
usually transient, increases in blood urea nitrogen and serum creatinine when taking ALTACE, particularly when
ALTACE was given concomitantly with a diuretic [see Warnings and Precautions (5.3)].
Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ALTACE [see
Warnings and Precautions (5.1) ].
Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes
suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased
salivation, and taste disturbance.
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Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever),
photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and
Stevens-Johnson syndrome.
Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia,
neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA,
an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity,
rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has
been reported.
Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.
6.2 Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during
ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal
relationship is unknown.
6.3 Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE
alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5%
of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases
required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal
insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to
be especially likely in patients with renal artery stenosis [see Warnings and Precautions (5.3)]. As ramipril decreases
aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing
diuretics with caution, and monitor the patient’s serum potassium frequently [see Warnings and Precautions (5.8)].
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%,
respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving
ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated
with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been
reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials,
less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or
abnormal liver-function tests.
7 DRUG INTERACTIONS
7.1 Diuretics
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an
excessive reduction of blood pressure after initiation of therapy with ALTACE. The possibility of hypotensive effects
with ALTACE can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to
initiation of treatment with ALTACE. If this is not possible, reduce the starting dose [see Dosage and Administration (2)].
ALTACE can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if
concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
7.2 Other Antihypertensive Agents
Limited experience in controlled and uncontrolled trials combining ALTACE with a calcium channel blocker, a loop
diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE
inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower
blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart
rate).
Reference ID: 3396356
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In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased
incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups
receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual
Blockade of the Renin-Angiotensin-Aldosterone System (5.7)].
7.3 Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors
during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also
used, the risk of lithium toxicity may be increased.
7.4 Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in
patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including
ALTACE.
7.5 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function,
co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result
in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal
function periodically in patients receiving ramipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
7.6 Aliskiren
Do not co-administer aliskiren with ALTACE in patients with diabetes. Avoid concomitant use of aliskiren with
ALTACE in patients with renal impairment (GFR <60 mL/min/1.73 m2) [see Warnings and Precautions (5.7)].
7.7 mTOR Inhibitors
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. [see
Warnings and Precautions (5.1)]
7.8 Other
Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine,
indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation
effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum
phenprocoumon levels or interfere with the patients’ state of anticoagulation.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal
renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with
fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,
hypotension, renal failure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible. These
adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not
distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management
of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for
a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess
the intra-amniotic environment. If oligohydramnios is observed, discontinue ALTACE unless it is considered life-saving
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be
aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely
observe infants with histories of in utero exposure to ALTACE for hypotension, oliguria, and hyperkalemia [see Use in
Specific Populations (8.4)].
8.3 Nursing Mothers
Ingestion of a single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in
breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single
dose, do not use ALTACE in nursing mothers.
8.4 Pediatric Use
Neonates with a history of in utero exposure to ALTACE:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange
transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal
function. Ramipril, which crosses the placenta, can be removed from the neonatal circulation by these means, but limited
experience has not shown that such removal is central to the treatment of these infants.
Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in
very young rats given a single dose of ALTACE.
8.5 Geriatric Use
Of the total number of patients who received ALTACE in U.S. clinical studies of ALTACE, 11.0% were ≥65 years of age
while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients
and younger patients, and other reported clinical experience has not identified differences in responses between the elderly
and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under
the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
8.6 Renal Impairment
A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment
who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of
creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and
severe impairment (<15 mL/min). On average, the AUC0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold
higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the
group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted
downward in patients with moderate-to-severe renal impairment.
10 OVERDOSAGE
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as
high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most
likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might
accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be
effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but
angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril
is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of
normal saline solution.
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar
organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3
phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell
contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell
contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is: structural formula
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by
hepatic cleavage of the ester group.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl
dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II
also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II,
which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up
to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from
baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline
greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide
for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and
approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see Warnings and
Precautions (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity.
The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE
activity, thereby reducing angiotensin II formation in tissue and plasma.
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated.
While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the renin
angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension.
Although ALTACE was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin
hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than
non-Black patients.
12.2 Pharmacodynamics
Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after
dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause
plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining
24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE
binding sites by ramiprilat and relatively slow release from those sites.
12.3 Pharmacokinetics
Absorption
Following oral administration of ALTACE, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The
extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal
tract, although the rate of absorption is reduced.
In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved
in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the
concomitant liquid or food.
Distribution
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak
plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is
about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of
0.01 µg/mL–10 µg/mL.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril,
and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which
are inactive.
Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The
24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg-20 mg dose range. The absolute
bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared
with the same dose of ramipril given intravenously.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state
concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses
(2.5 mg), but the difference is clinically insignificant.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase,
terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral
compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent
binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent
elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal
elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the
ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ALTACE
5 mg-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and
trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these
patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of
diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic
function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
Excretion
After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and
about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or
unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the
administered dose is recovered in urine as unchanged ramipril.
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function.
Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough
ramiprilat levels and slightly longer times to peak concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of
up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are
about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No
mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in
a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and
degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as
500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body
surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the
recommended human dose.
14 CLINICAL STUDIES
14.1 Hypertension
ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for
hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and
standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is
infrequent, although it can occur in patients who are salt- and/or volume-depleted [see Warnings and Precautions (5.5)].
Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with
either agent alone.
In single-dose studies, doses of 5 mg–20 mg of ALTACE lowered blood pressure within 1–2 hours, with peak reductions
achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12
weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing
systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of
peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titration study comparing
divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive
effect with once-daily dosing is not adequately maintained.
In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements.
The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt
withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other
ACE inhibitors, beta-blockers, and thiazide diuretics. ALTACE was approximately as effective as other ACE inhibitors
and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than
ramipril.
ALTACE was less effective in blacks than in Caucasians. The effectiveness of ALTACE was not influenced by age, sex,
or weight.
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied
by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial design study
conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a
major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes
that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low
HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment
with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low
ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg
orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction,
stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3
components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to
the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of
treatment.
Table 3. Summary of Combined Components and Endpoints—HOPE Study
Outcome
Placebo
(N=4652)
n (%)
ALTACE
(N=4645)
n (%)
Relative Risk
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
826 (17.8%)
651 (14.0%)
0.78 (0.70–0.86)
P=0.0001
Component
Endpoint
Death from
cardiovascular causes
377 (8.1%)
282 (6.1%)
0.74 (0.64–0.87)
P=0.0002
Myocardial infarction
570 (12.3%)
459 (9.9%)
0.80 (0.70–0.90)
P=0.0003
Stroke
226 (4.9%)
156 (3.4%)
0.68 (0.56–0.84)
P=0.0002
Overall Mortality
Death from any cause
569 (12.2%)
482 (10.4%)
0.84 (0.75–0.95)
P=0.005
Reference ID: 3396356
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Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from
Cardiovascular Causes in the Ramipril Group and the Placebo Group graph
ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease
(e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient
data to determine whether or not ALTACE was equally effective in ethnic subgroups.
This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor.
Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to those in the
overall study population.
Table 4. Summary of Combined Endpoints and Components in Diabetics—HOPE Study
Outcome
Placebo
(N=1769)
n (%)
ALTACE
(N=1808)
n (%)
Relative Risk
Reduction
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
351 (19.8%)
277 (15.3%)
0.25 (0.12–0.36)
P=0.0004
Component
Endpoint
Death from
cardiovascular causes
172 (9.7%)
112 (6.2%)
0.37 (0.21–0.51)
P=0.0001
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Myocardial infarction
229 (12.9%)
185 (10.2%)
0.22 (0.06–0.36)
P=0.01
Stroke
108 (6.1%)
76 (4.2%)
0.33 (0.10–0.50)
P=0.007
Figure 2. The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction,
Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups graph
Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the
number of patients in each group. The dashed line indicates overall relative risk.
The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, beta-
blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3 Heart Failure Post-Myocardial Infarction
ALTACE was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-
blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2–9 days after an acute
myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction.
Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or
valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had
received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of
treatment was 5 days.
Patients randomized to ALTACE treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused
undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a
target regimen (achieved in 77% of patients randomized to ALTACE) of 5 mg twice daily. Patients were then followed
for an average of 15 months, with the range of follow-up between 6 and 46 months.
The use of ALTACE was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of
the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of
congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively.
The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the
initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in
patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80%
of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers
(about 15%), and digoxin (about 12%).
16 HOW SUPPLIED/STORAGE AND HANDLING
ALTACE is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules. Descriptions of ALTACE capsules are
summarized below.
Capsule Strength
Capsule Color
Package
Configuration
NDC#
1.25 mg
yellow
Bottle of 100
61570-110-01
2.5 mg
orange
Bottle of 100
61570-111-01
5 mg
red
Bottle of 100
61570-112-01
10 mg
Process Blue
Bottle of 100
61570-120-01
Dispense in well-closed container with safety closure.
Store at controlled room temperature (59º–86ºF).
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the
first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes,
lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing
physician.
17.2 Neutropenia
Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of
neutropenia.
17.3 Symptomatic Hypotension
Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported.
Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can
lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17.4 Pregnancy
Female patients of childbearing age should be told about the consequences of exposure to Altace during pregnancy.
Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to
their physicians as soon as possible.
17.5 Hyperkalemia
Advise patients not to use salt substitutes containing potassium without consulting their physician. company logo
LAB-0581-2.1
Reference ID: 3396356
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:46:16.344090
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019901s063lbl.pdf', 'application_number': 19901, 'submission_type': 'SUPPL ', 'submission_number': 63}
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